Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family

ABSTRACT

Described are compounds of the following formula and a method of inhibiting epidermal growth factor by treating, with an effective inhibiting amount, a mammal, in need thereof, a compound of the formula:wherein the formula terms are described in the specification and wherein the members in the aforementioned structure are defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 08/358,352, filed Dec.23, 1994 now U.S. Pat. No. 5,679,683 which is a continuation-in-part ofU.S. Ser. No. 08/186,735, filed Jan. 25, 1994 and U.S. Ser. No.08/186,745, filed Jan. 25, 1994 both applications now abandoned.

TECHNICAL FIELD

The present invention relates to tricyclic heteroaromatic compoundswhich inhibit the epidermal growth factor receptor and related receptorsand, in particular, their tyrosine kinase enzymic activity.

BACKGROUND ART

Cancer is generally a disease of the intracellular signalling system, orsignal transduction mechanism. Cells receive instructions from manyextracellular sources, instructing them to either proliferate or not toproliferate. The purpose of the signal transduction system is to receivethese and other signals at the cell surface, get them into the cell, andthen pass the signals on to the nucleus, the cytoskeleton, and transportand protein synthesis machinery. The most common cause of cancer is aseries of defects, either in these proteins, when they are mutated, orin the regulation of the quantity of the protein in the cell such thatit is over or under produced. Most often, there are key lesions in thecell which lead to a constitutive state whereby the cell nucleusreceives a signal to proliferate, when this signal is not actuallypresent. This can occur through a variety of mechanisms. Sometimes thecell may start to produce an authentic growth factor for its ownreceptors when it should not, the so-called autocrine loop mechanism.Mutations to the cell surface receptors, which usually signal into thecell by means of tyrosine kinases, can lead to activation of the kinasein the absence of ligand, and passing of a signal which is not reallythere. Alternatively, many surface kinases can be overexpressed on thecell surface leading to an inappropriately strong response to a weaksignal. There are many levels inside the cell at which mutation oroverexpression can lead to the same spurious signal arising in the cell,and there are many other kinds of signalling defect involved in cancer.This invention touches upon cancers which are driven by the threemechanisms just described, and which involve cell surface receptors ofthe epidermal growth factor receptor tyrosine kinase family (EGFR). Thisfamily consists of the EGF receptor (also known as Erb-B1), the Erb-B2receptor, and its constituitively active oncoprotein mutant Neu, theErb-B3 receptor and the Erb-B4 receptor. Additionally, other biologicalprocesses driven through members of the EGF family of receptors can alsobe treated by compounds of the invention described below.

The EGFR has as its two most important ligands Epidermal Growth Factor(EGF) and Transforming Growth Factor alpha (TGFalpha). The receptorsappear to have only minor functions in adult humans, but are apparentlyimplicated in the disease process of a large portion of all cancers,especially colon and breast cancer. The closely related Erb-B2 Erb-B3and Erb-B4 receptors have a family of Heregulins as their major ligands,and receptor overexpression and mutation have been unequivocallydemonstrated as the major risk factor in poor prognosis breast cancer.Additionally, it has been demonstrated that all four of the members ofthis family of receptors can form heterodimeric signalling complexeswith other members of the family, and that this can lead to synergistictransforming capacity if more than one member of the family isoverexpressed in a malignancy. Overexpression of more than one familymember has been shown to be relatively common in human malignancies.

The proliferative skin disease psoriasis has no good cure at present. Itis often treated by anti-cancer agents such as methotrexate, which havevery serious side effects, and which are not very effective at thetoxicity-limited doses which have to be used. It is believedthat,TGFalpha is the major growth factor overproduced in psoriasis,since 50% of transgenic mice which overexpress TGF alpha developpsoriasis. This suggests that a good inhibitor of EGFR signalling couldbe used as an antipsoriatic agent, preferably, but not necessarily, bytopical dosing.

EGF is a potent mitogen for renal tubule cells. Fourfold increases inboth EGF urinary secretion and EGF mRNA have been noted in mice withearly stage streptozoicin-induced diabetes. In addition increasedexpression of the EGFR has been noted in patients with proliferativeglomerulonephritis (Roychaudhury et al. Pathology 1993, 25, 327). Thecompounds of the current invention should be useful in treating bothproliferative glomerulonephritis and diabetes-induced renal disease.

Chronic pancreatitis in patients has been reported to correlate withlarge increases in expression for both EGFR and TGF alpha. (Korc et al.Gut 1994, 35, 1468). In patients showing a more severe form of thedisease, typified by an enlargement of the head of the pancreas, therewas also shown to be overexpression of the erb-B2 receptor (Friess etal. Ann. Surg. 1994, 220, 183). The compounds of the current inventionshould prove useful in the treatment of pancreatitis.

In the processes of blastocyte maturation, blastocyte implantation intothe uterine endometrium, and other periimplantation events, uterinetissues produce EGF and TGF alpha (Taga Nippon Sanka Fujinka GakkaiZasshi 1992, 44, 939), have elevated levels of EGFR (Brown et al.Endocrinology, 1989, 124, 2882), and may well be induced to produceheparin-binding EGF by the proximity of the developing, but notarrested, blastocyte (Das et al. Development 1994, 120, 1071). In turnthe blastocyte has quite a high level of TGF alpha and EGFR expression(Adamson Mol. Reprod. Dev. 1990, 27, 16). Surgical removal of thesubmandibular glands, the major site of EGF secretion in the body, andtreatment with anti-EGFR monoclonal antibodies both greatly reducefertility in mice (Tsutsumi et al. J. Endocrinology 1993, 138, 437), byreducing successful blastocyte implantation. Therefore, compounds of thecurrent invention should prove to have useful contraceptive properties.

PCT patent application Nos. WO92/07844 published May 14, 1992 andWO92/14716 published Sep. 3, 1992 describe 2,4-diaminoquinazoline aspotentiators of chemotherapeutic agents in the treatment of cancer.

PCT published application No. WO92/20642 published Nov. 26, 1992discloses bismono- and bicyclic aryl and heteroaryl compounds whichinhibit EGF and/or PDGF receptor tyrosine kinase.

It is an object of the present invention to inhibit the mitogeniceffects of epidermal growth factor utilizing an effective amount oftricyclic pyrimidine derivatives, in particular fused heterocyclicpyrimidine derivatives.

It is another object of the present invention to describe tricyclicpyrimidine derivatives, in particular fused heterocyclic pyrimidinederivatives, as inhibitors of the EGF, Erb-B2 and Erb-B4 receptortyrosine kinases.

It is yet another object of the present invention to describe tricyclicpyrimidine derivatives, in particular fused heterocyclic pyrimidinederivatives, that are useful at low dosages as inhibitors of EGF-inducedmitogenesis. This therefore leads to a further object of compoundshaving extremely low cytotoxicity.

It is a further object of the present invention to describe tricyclicpyrimidine derivatives, in particular fused heterocyclic pyrimidinederivatives, that are useful in suppressing tumors, especially breastcancers, where mitogenesis is heavily driven by EGFR family members.

It is another object of the present invention to describe tricyclicpyrimidine derivatives, in particular fused heterocyclic pyrimidinederivatives, that have utility as chronic therapy as inhibitors ofEGF-induced responses.

It is another object of the current invention to describe tricyclicpyrimidine derivatives, in particular fused heterocyclic pyrimidinederivatives, that have utility as therapeutic agents againstproliferative overgrowth diseases, including but not limited to,synovial pannus invasion in arthritis, vascular restenosis andangiogenesis. Additional utility of these materials is for pancreatitisand kidney disease as well as contraception.

SUMMARY OF THE INVENTION

Described is a method to inhibit epidermal growth factor by treating,with an effective inhibiting amount, a mammal, in need thereof, acompound of the following formula:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle;

A, B, D and E can all be carbon, or up to two of them can be nitrogen,whereupon the remaining atoms must be carbon, or any two contiguouspositions in A-E can be a single heteroatom, N, O or S, forming a fivemembered fused ring, in which case one of the two remaining atoms mustbe carbon, and the other can be either carbon or nitrogen, except thatthe case where A and B taken together, and D and E taken separately areall three nitrogen atoms;

X=O, S, NH or NR⁹, such that R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂,lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbonatoms);

R¹=H or lower alkyl;

n=0, 1 or 2;

if n=2, R¹ can be independently H or lower alkyl on either linkingcarbon atom, and both R and S stereocentres on either linker areincluded;

R² is lower alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms),lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms), nitro,halo, lower perfluoroalkyl (1-4 carbon atoms), hydroxy, lower acyloxy(1-4 carbon atoms; —O—C(O)—R), amino, lower mono or dialkylamino (1-4carbon atoms), lower mono or dicycloalkylamino (3-8 carbon atoms),hydroxymethyl, lower acyl (1-4 carbon atoms; —C(O)R), cyano, lowerthioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4 carbon atoms),lower sulfonylalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), sulfinylcycloalkyl (3-8 carbon atoms), sulfonylcycloalkyl (3-8carbon atoms), mercapto, lower alkoxycarbonyl (1-4 carbon atoms),cycloalkoxycarbonyl (3-8 carbon atoms), lower alkenyl (2-4 carbonatoms), cycloalkenyl (4-8 carbon atoms), lower alkynyl (2-4 carbonatoms), or two R² taken together can form a carbocyclic ring of 5-7members; and

m=0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl,pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl,benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl andquinazolinyl;

R³ , R⁴, R⁵ and R⁶ are independently, not present, H, lower alkyl (1-4carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbonatoms), cycloalkoxy (3-8 carbon atoms), hydroxy, lower acyloxy (1-4carbon atoms), amino, lower mono or dialkylamino (1-4 carbon atoms),lower mono or dicycloalkylamino (3-8 carbon atoms), lower alkyl (1-4carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonate (—OC(O)OR)where R is alkyl of from 1-4 carbon atoms or cycloalkyl of from 3-8carbon atoms;

or ureido or thioureido or N or O linked urethane any one of which isoptionally substituted by mono or di-lower alkyl (1-4 carbon atoms) orcycloalkyl (3-8 carbon atoms);

lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbon atoms),mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N- and/or N′-mono- or di lower alkylhydrazino (1-4 carbon atoms), lower acylamino(1-4 carbon atoms), hydroxylamino, N- and/or C- mono- or di loweralkylhydroxylamino (1-4 carbon atoms), or taken together can bemethylene-, ethylene- or propylenedioxy, or taken together form a fusedpyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino orthiomorpholino ring;

R⁷ and R⁸ can be independently as appropriate, lone pairs of electrons,H, or lower alkyl;

any lower alkyl group substituent on any of the substituents in R³—R⁸which contain such a moiety can be optionally substituted with one ormore of hydroxy, amino, lower monoalkylamino, lower dialkylamino,N-pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino,N-thiomorpholino or N-piperazino groups;

if one or two of A through E are N, then if any of R³—R⁶ is on aneighboring C atom to one of the N atoms, that substituent cannot beeither OH or SH; and

R¹⁰ is H or lower alkyl (1-4 carbon atoms), amino or lower mono- ordialkylamino (1-4 carbon atoms);

if any of the substitutents R¹, R², R³ or R⁴ contain chiral centers, orin the case of R¹ create chiral centers on the linking atoms, then allstereoisomers thereof both separately and as racemic and/ordiastereoisomeric mixtures are included;

or a pharmaceutical salt or hydrate thereof.

The invention pertains to the compounds, per se:

with the proviso that the ring containing A-E is aromatic;

and with the proviso that if A and B taken together and E are nitrogen,and if neither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=Hand Ar=Ph, then one of the imidazole nitrogen atoms must have asubstituent from the R³—R⁶ group other than lone pair or hydrogen;

and with the proviso that if A-E are carbon, and Y is a bond, and Z issulfur, and X=NH, and n=0, then Ar cannot be unsubstituted phenyl,unsubstituted or substituted pyridyl or unsubstituted or substitutedpyrimidyl.

Preferably, the compounds are subject to additional provisos:

with the proviso that if A-E are carbon, Y and Z cannot be bothcarbon-or one ethylidene and the other a bond, unless at least one ofR³—R⁶ is not hydrogen;

with the proviso that if A-E are carbon one of Y and Z cannot benitrogen, substituted with hydrogen, and the other a bond.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an effect of Example 1 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma;

FIG. 2 is an effect of Examples 6 and 17 on EGF receptorautophosphorylation in A431 human epidermoid carcinoma;

FIG. 3 is an effect of Example 8 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma;

FIG. 4 is an effect of Example 10 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma;

FIG. 5 is an effect of Example 15 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma;

FIG. 6 is an effect of Example 25 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma;

FIG. 7 is an effect of Example 28 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma;

FIG. 8 is an effect of Example 29 on EGF receptor autophosphorylation inA431 human epidermoid carcinoma; and

FIG. 9 is an effect of Examples 6 and 17 on soft agar clone formation ofMDA-MB-468 human breast carcinoma.

DESCRIPTION OF PREFERRED EMBODIMENTS

Nomenclature and Numbering as Used Herein

Nomenclature. All tricycles containing a benzene ring fused directly tothe pyrimidine ring have been named as quinazoline derivatives. Allother tricycles are named as pyrimidine derivatives, either fused to abicyclic nucleus such as indole or benzothiophene, or to two separatemonocyclic heterocycles such as pyridothiophene. In such cases the firstring given is always the one distal to the pyrimidine ring.

Ring fusion numbers. For quinazoline derivatives the quinazoline nucleusis lettered counterclockwise with the N1-C2 bond being a, and the threepossible ring fusion positions being f, g and h. The C-ring is numbered1-5/6 from its highest atomic weight heteroatom, with the ring fusionnumbering being decided by the numbered bridgehead atom which firstmeets the counterclockwise flow of the quinazoline lettering.

For systems with three fused heteroaromatic rings, the pyrimidine ring(A) is always chosen as the root system and is d-fused to the B-ringlettering in a clockwise direction. The central B-ring is numbered1-5/6, starting at the heteroatom, and going first via the B/C ringjunction and then the B/A ring junction. It can be numbered eitherclockwise, when the heteroatom is at the bottom, or counterclockwise,when the heteroatom is at the top, (as is illustrated above), and thering fusion numbering is decided by the numbered bridgehead atom whichfirst meets the clockwise flow of the pyrimidine lettering. The C-ringis numbered 1′-5′/6′ from the highest priority heteroatom, towards lowerpriority heteroatoms if present, and if there are no other heteroatoms,in the direction which gives the lowest numbering to the ring junction.The first C-ring fusion number is that of the bridgehead atom which hasthe lowest numbering in the B-ring numbering system. In the first set ofparentheses the C-ring numbers of the B/C bridgehead atoms are given,followed after the colon by the B-ring numbers for the same atoms. Thesecond set of parentheses contain the B-ring numbers for theA/B-bridgehead atoms, followed after the dash by the shared bond in theA-ring lettering system. Thus, the example above illustrates a[5′,4′:2,3] [5,6-d]tricyclic system.

Substituent Numbering. In all of the examples, the numbering is takenfrom the bottom nitrogen of the pyrimidine A ring as 1, and then allnonbridgehead atoms are counted consecutively in a counterclockwisedirection from that point, as illustrated above for a 6,6,6-system bythe bolded numbers.

1. A preferred form of the invention has n=0, A-E, Y & Z being carbon,X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogen. Asuitable ring structure is:

2. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as oxygen, the remaining pair both beingcarbon, along with Y and Z, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate. A suitable ring structure is:

3. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as sulfur, the remaining pair both being iscarbon, along with Y and Z, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate.

4. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as nitrogen, the remaining pair both beingcarbon, along with Y and Z, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or optionally lower alkyl if onnitrogen. A suitable ring structure is:

5. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and E as nitrogen, or D & E taken together as oxygenand A as nitrogen, Y and Z both carbon, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate.

6. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and E as nitrogen, or D & E taken together as sulfurand A as nitrogen, Y and Z both carbon, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate. A suitable ring structure is:

7. Another preferred form of the invention has n=0 or 1, A & B takentogether, and E as nitrogen, Y and Z both carbon, X=NH, Ar a benzenering, optionally substituted, and R⁵—R⁸ hydrogen or optionally loweralkyl if on nitrogen. or a lone pair of electrons where appropriate.

8. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and D as nitrogen, or D & E taken together as oxygenand B as nitrogen, Y and Z both carbon, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

9. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and D as nitrogen, or D & E taken together as sulfurand B as nitrogen, Y and Z both carbon, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

10. Another preferred form of the invention has n=0 or 1, A & B takentogether, and D as nitrogen, or D & E taken together, and B as nitrogen,Y and Z both carbon, X=NH, Ar a benzene ring, optionally substituted,and R⁵—R⁸ hydrogen, lower alkyl, or a lone pair of electrons whereappropriate. A suitable ring structure is:

11. Another preferred form of the invention has n=0, A & B takentogether, with D & E taken separately as nitrogen, Y and Z both carbon,X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogen oroptionally lower alkyl if on nitrogen, or a lone pair of electrons whereappropriate.

12. Another preferred form of the invention has n=0 or 1, with one of A,B, D or E as nitrogen, the remaining three being carbon, along with Yand Z, X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸hydrogen or a lone pair of electrons where appropriate.

13. Another preferred form of the invention has n=0, with any two of A,B, D or E as nitrogen, the remaining two being carbon, along with Y andZ, X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogenor a lone pair of electrons where appropriate.

14. Another preferred form of the invention has n=0, A-E, and one of Yand Z being carbon, the other nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate. A suitable ring structure is:

15. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as oxygen, the remaining pair both beingcarbon, along with one of Y and Z, the other being nitrogen, X=NH, Ar abenzene ring, optionally substituted, and R⁵—R⁸ hydrogen or a lone pairof electrons where appropriate. A suitable structure is:

16. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as sulfur, the remaining pair both beingcarbon, along with one of Y and Z, the other being nitrogen, X=NH, Ar abenzene ring, optionally substituted, and R⁵—R⁸ hydrogen or a lone pairof electrons where appropriate.

17. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as nitrogen, the remaining pair both beingcarbon, along with one of Y and Z, the other being nitrogen, X=NH, Ar abenzene ring, optionally sub-stituted, and R⁵—R⁸ hydrogen, or optionallylower alkyl if on nitrogen in the pyrrole ring, or a lone pair ofelectrons where appropriate.

18. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and E as nitrogen, or D & E taken together as oxygenand A as nitrogen, one of Y and Z being carbon the other nitrogen, X=NH,Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogen or a lonepair of electrons where appropriate. A suitable ring structure is:

19. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and E as nitrogen, or D & E taken together as sulfurand A as nitrogen, one of Y and Z being carbon the other nitrogen, X=NH,Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogen or a lonepair of electrons where appropriate.

20. Another preferred form of the invention has n=0 or 1, A & B takentogether, and E as nitrogen, one of Y and Z being carbon the othernitrogen, X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸hydrogen or optionally lower alkyl if on nitrogen or a lone pair ofelectrons where appropriate.

21. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and D as nitrogen, or D & E taken together as oxygenand B as nitrogen, one of Y and Z being carbon the other nitrogen, X=NH,Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogen, loweralkyl, or a lone pair of electrons where appropriate.

22. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and D as nitrogen, or D & E taken together as sulfurand B as nitrogen, one of Y and Z being carbon the other nitrogen, X=NH,Ar a benzene ring, optionally substituted, and R⁵—R⁸ hydrogen, loweralkyl, or a lone pair of electrons where appropriate.

23. Another preferred form of the invention has n=0 or 1, A & B takentogether, and D as nitrogen, or D & E taken together, and B as nitrogen,one of Y and Z being carbon the other nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

24. Another preferred form of the invention has n=0 or 1, with one of A,B, D or E as nitrogen, the remaining three being carbon, along with oneof Y and Z, the other being nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate. A suitable ring structure is:

25. Another preferred form of the invention has n=0, with any two of A,B, D or E as nitrogen, the remaining two being carbon, along with one ofY and Z, the other being nitrogen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate.

26. A preferred form of the invention has n=0, A-E carbon, Y and Znitrogen, X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸hydrogen or a lone pair of electrons where appropriate. A suitable ringstructure is:

27. Another preferred form of the invention has n=0 or 1, A-E beingcarbon, one of Y & Z being ethylidene, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen. A suitable ring structureis:

28. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as oxygen, the remaining pair both beingcarbon, one of Y & Z being ethylidene, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate.

29. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as sulfur, the remaining pair both beingcarbon, one of Y & Z being ethylidene, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate.

30. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as nitrogen, the remaining pair both beingcarbon, one of Y & Z being ethylidene, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or optionally lower alkyl ifon nitrogen.

31. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and E as nitrogen, or D & E taken together as oxygenand A as nitrogen, one of Y & Z being ethylidene, X=NH, Ar a benzenering, optionally substituted, and R⁵—R⁸ hydrogen or a lone pair ofelectrons where appropriate.

32. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and E as nitrogen, or D & E taken together as sulfurand A as nitrogen, one of Y & Z being ethylidene, X=NH, Ar a benzenering, optionally substituted, and R⁵—R⁸ hydrogen or a lone pair ofelectrons where appropriate.

33. Another preferred form of the invention has n=0, A & B takentogether, and E as nitrogen, one of Y & Z being ethylidene, X=NH, Ar abenzene ring, optionally substituted, and R⁵—R⁸ hydrogen or optionallylower alkyl if on nitrogen or a lone pair of electrons whereappropriate. A suitable ring structure is:

34. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and D as nitrogen, or D & E taken together as oxygenand B as nitrogen, one of Y & Z being ethylidene, X=NH, Ar a benzenering, optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lonepair of electrons where appropriate.

35. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and D as nitrogen, or D & E taken together as sulfurand B as nitrogen, one of Y & Z being ethylidene, X=NH, Ar a benzenering, optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lonepair of electrons where appropriate. A suitable ring structure is:

36. Another preferred form of the invention has n=0 or 1, A & B takentogether, and D as nitrogen, or D & E taken together, and B as nitrogen,one of Y & Z being ethylidene, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pair ofelectrons where appropriate.

37. Another preferred form of the invention has n=0 or 1, with one of A,B, D or E as nitrogen, the remaining three being carbon, one of Y & Zbeing ethylidene, X=NH, Ar a benzene ring, optionally substituted, andR⁵—R⁸ hydrogen or a lone pair of electrons where appropriate.

38. Another preferred form of the invention has n=0, with any two of A,B, D or E as nitrogen, the remaining two being carbon, one of Y & Zbeing ethylidene, X=NH, Ar a benzene ring, optionally substituted, andR⁵—R⁸ hydrogen or a lone pair of electrons where appropriate.

39. Another preferred form of the invention has n=0 or 1, A-E beingcarbon, one of Y & Z being sulfur, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate. A suitable ring structure is:

40. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as oxygen, the remaining pair both beingcarbon, one of Y & Z being sulfur, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate.

41. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as sulfur, the remaining pair both beingcarbon, one of Y & Z being sulfur, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate.

42. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as nitrogen, the remaining pair both beingcarbon, one of Y & Z being sulfur, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate or optionally lower alkyl if on nitrogen.

43. Another preferred form of the invention has n=0 or 1, A & R takentogether as oxygen, and E as nitrogen, or D & E taken together as oxygenand A as nitrogen, one of Y & Z being sulfur, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate.

44. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and E as nitrogen, or D & E taken together as sulfurand A as nitrogen, one of Y & Z being sulfur, X=NH, Ar a is benzenering, optionally substituted, and R⁵—R⁸ hydrogen or a lone pair ofelectrons where appropriate. A suitable ring structure is:

45. Another preferred form of the invention has n=0, A & B takentogether, and E as nitrogen, one of Y & Z being sulfur, X=NH, Ar abenzene ring, optionally substituted, and R⁵—R⁸ hydrogen or optionallylower alkyl if on nitrogen. or a lone pair of electrons whereappropriate.

46. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and D as nitrogen, or D & E taken together as oxygenand B as nitrogen, one of Y & Z being sulfur, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

47. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and D as nitrogen, or D & E taken together as sulfurand B as nitrogen, one of Y & Z being sulfur, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

48. Another preferred form of the invention has n=0 or 1, A & B takentogether, and D as nitrogen, or D & E taken together, and B as nitrogen,one of Y & Z being sulfur, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pair ofelectrons where appropriate.

49. Another preferred form of the invention has n=0 or 1, with one of A,B, D or E as nitrogen, the remaining three being carbon, one of Y & Zbeing sulfur, X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸hydrogen or a lone pair of electrons where appropriate.

50. Another preferred form of the invention has n=0 or 1, A-E beingcarbon, one of Y & Z being nitrogen, X=NH, Ar a benzene ring, optionallysubstituted and R⁵—R⁸ hydrogen, or optionally lower alkyl if onnitrogen.

51. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as oxygen, the remaining pair both beingcarbon, one of Y & Z being nitrogen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate, or optionally lower alkyl if on nitrogen.

52. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as sulfur, the remaining pair both beingcarbon, one of Y & Z being nitrogen, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate, or optionally lower alkyl if on nitrogen.

53. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as nitrogen, the remaining pair both beingcarbon, one of Y & Z being nitrogen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or optionally lower alkyl if onnitrogen.

54. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and E as nitrogen, or D & E taken together as oxygenand A as nitrogen, one of Y & Z being nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate, or optionally lower alkyl if on nitrogen. A suitablering structure is:

55. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and E as nitrogen, or D & E taken together as sulfurand A as nitrogen, one of Y & Z being nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate, or optionally lower alkyl if on nitrogen.

56. Another preferred form of the invention has n=0, A & B takentogether, and E as nitrogen, one of Y & Z being nitrogen, X=NH, Ar abenzene ring, optionally substituted, and R⁵—R⁸ hydrogen or optionallylower alkyl if on nitrogen or a lone pair of electrons whereappropriate.

57. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and D as nitrogen, or D & E taken together as oxygenand B as nitrogen, one of Y & Z being nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

58. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and D as nitrogen, or D & E taken together as sulfurand B as nitrogen, one of Y & Z being nitrogen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

59. Another preferred form of the invention has n=0 or 1, A & B takentogether, and D as nitrogen, or D & E taken together, and B as nitrogen,one of Y & Z being nitrogen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pair ofelectrons where appropriate.

60. Another preferred form of the invention has n=0 or 1, with one of A,B, D or E as nitrogen, the remaining three being carbon, one of Y & Zbeing nitrogen, X=NH, Ar a benzene ring, optionally substituted, andR⁵R⁸ hydrogen or a lone pair of electrons where appropriate.

61. Another preferred form of the invention has n=0 or 1, A-E beingcarbon, one of Y & Z being oxygen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate. A suitable ring structure is:

62. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as oxygen, the remaining pair both beingcarbon, one of Y & Z being oxygen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate.

63. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as sulfur, the remaining pair both beingcarbon, one of Y & Z being oxygen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate.

64. Another preferred form of the invention has, n=0 or 1, with one of A& B or D & E taken together as nitrogen, the remaining pair both beingcarbon, one of Y & Z being oxygen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen or a lone pair of electrons whereappropriate or optionally lower alkyl if on nitrogen.

65. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and E as nitrogen, or D & E taken together as oxygenand A as nitrogen, one of Y & Z being oxygen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate.

66. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and E as nitrogen, or D & E taken together as sulfurand A as nitrogen, one of Y & Z being oxygen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen or a lone pair of electronswhere appropriate. A suitable ring structure is:

67. Another preferred form of the invention has n=0, A & B takentogether, and E as nitrogen, one of Y & Z being oxygen, X=NH, Ar abenzene ring, optionally substituted, and R⁵—R⁸ hydrogen or optionallylower alkyl if on nitrogen or a lone pair where appropriate.

68. Another preferred form of the invention has n=0 or 1, A & B takentogether as oxygen, and D as nitrogen, or D & E taken together as oxygenand B as nitrogen, one of Y & Z being oxygen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

69. Another preferred form of the invention has n=0 or 1, A & B takentogether as sulfur, and D as nitrogen, or D & E taken together as sulfurand B as nitrogen, one of Y & Z being oxygen, X=NH, Ar a benzene ring,optionally substituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pairof electrons where appropriate.

70. Another preferred form of the invention has n=0 or 1, A & B takentogether, and D as nitrogen, or D & E taken together, and B as nitrogen,one of Y & Z being oxygen, X=NH, Ar a benzene ring, optionallysubstituted, and R⁵—R⁸ hydrogen, lower alkyl, or a lone pair ofelectrons where appropriate.

71. Another preferred form of the invention has n=0 or 1, with one of A,B, D or E as nitrogen, the remaining three being carbon, one of Y & Zbeing oxygen, X=NH, Ar a benzene ring, optionally substituted, and R⁵—R⁸hydrogen or a lone pair of electrons where appropriate.

MOST PREFERRED FORMS OF THE INVENTION

1. A most preferred form of the invention is one where A-E, Y and Z areall carbon, n=0, X=NH, Ar is phenyl, R² is meta-bromo, m=1, and R³—R⁸are all hydrogen.

2. A most preferred form of the invention is one where A-E, Y and Z areall carbon, n=1, X=NH, Ar is phenyl, R¹ is [R]—CH₃ and R²—R⁸ are allhydrogen.

3. A most preferred form of the invention is one where A and B arecarbon, D and E taken together are nitrogen, Y and Z are carbon, n=0,X=NH, Ar is phenyl, R¹ is meta-bromo, m=1, and R⁴—R⁸ are all hydrogen.

4. A most preferred form of the invention is one where A and B takentogether are sulfur, E is nitrogen, D, Y and Z are carbon, n=0, X=NH, Aris phenyl, R² is meta-bromo, m=1, and R⁴ and R⁶—R⁸ are all hydrogen.

5. A most preferred form of the invention is one where A and B takentogether are oxygen, E is nitrogen, D, Y and Z are carbon, n=0, X=NH, Aris phenyl, R² is meta-bromo, m=1, and R⁴ and R⁶—R⁸ are all hydrogen.

6. A most preferred form of the invention is one where A and B takentogether are nitrogen, E is nitrogen, D, Y and Z are carbon, n=0, X=NH,Ar is phenyl, R² is meta-bromo, m=1, and R⁴ and R⁶—R⁸ are all hydrogen.

7. A most preferred form of the invention is one where A and B takentogether are nitrogen, D and E taken separately are nitrogen, Y and Zare carbon, n=0, X=NH, Ar is phenyl, R² is meta-bromo, m=1, and R⁶—R⁸are all hydrogen.

8. A most preferred form of the invention is one where A and B takentogether are nitrogen, E is nitrogen, Y and Z are carbon, n=0, X=NH, Aris phenyl, R² is meta-bromo, m=1, and R⁴, R⁷ and R⁸ are hydrogen and R⁶is methyl.

9. A most preferred form of the invention is one where A and B takentogether are nitrogen, E is nitrogen, Y and Z are carbon, n=0, X=NH, Aris phenyl, R² is meta-bromo, m=1, and R⁴, R⁷ and R⁸ are hydrogen and R⁵is methyl.

10. A most preferred form of the invention is one where A and E arenitrogen, B, D, Y and Z are all carbon, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, and R³—R⁸ are all hydrogen.

11. A most preferred form of the invention is one where A and B takentogether are nitrogen, E is nitrogen, Z is ethylidene, and Y a C—C bond,n=0, X=NH, Ar is phenyl, R² is meta-bromo, m=1, and R⁴ and R⁶—R⁸ are allhydrogen.

12. A most preferred form of the invention is one where A-E, are allcarbon, Z is sulfur, and Y a C—C bond, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, and R³—R⁶ are all hydrogen.

13. A most preferred form of the invention is one where A-E, are allcarbon, Z is sulfur, and Y a C—C bond, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, R⁵ is nitro R³, R⁴ and R⁶ are all hydrogen.

14. A most preferred form of the invention is one where A-E, are allcarbon, Z is sulfur, and Y a C—C bond, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, R⁵ is amino R³, R⁴ and R⁶ are all hydrogen.

15. A most preferred form of the invention is one where A-E, are allcarbon, Z is sulfur, and Y a C—C bond, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, R⁶ is methoxy and R³-R⁵ are all hydrogen.

16. A most preferred form of the invention is one where A is nitrogen, Dand E taken together, and Z are sulfur and Y a C—C bond, n=0, X=NH, Aris phenyl, R² is meta-bromo, m=1, and R³ is hydrogen.

17. A most preferred form of the invention is one where A-E, are allcarbon, Z is nitrogen, and Y a C—C bond, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, and R³—R⁶ and R⁸ are all hydrogen.

18. A most preferred form of the invention is one where A-E, are allcarbon, Y is nitrogen, and Z a C—C bond, n=0, X=NH, Ar is phenyl, R² ismeta-bromo, m=1, and R³—R⁶ and R⁸ are all hydrogen.

The compounds of the present invention are prepared according to anumber of alternative reaction sequences.

It is to be appreciated that in the tricyclic structure of Formula I,the ring having A-E is aromatic. By “aromatic” is meant that all membersof the ring share electrons and there is a resonance among the membersof the ring.

Preparative Routes to Compounds of the Invention

Scheme 1 for Preferred Group 1

Condensation of commercially available 3-amino-2-naphthoic acid withformamide gives the benzoquinazoline nucleus. (DMF is dimethylformamide). Conversion of the carbonyl to halide is followed bydisplacement with the appropriate amine side chain. Representativeexamples of compounds that can be made by this route are given in thetable below.

Scheme 2 for Preferred Group 4 [3,2-g] Isomer

Nitration of methyl 5-methyl-2-nitrobenzoate, and isomer separationgives the 2,4-dinitrobenzoate ester. This is converted to thecorresponding benzamide with methanolic ammonia, and both the amidenitrogen and the benzylic methyl are condensed with DMF di-t-butoxyacetal. On Raney Nickel reduction of both nitro groups to amines boththe pyrrole and pyrimidone rings spontaneously cyclize to give thedesired pyrrolo[3,2-g]quinazolone. Conversion on to the chloride withPOCl₃ is followed by displacement of the chlorine with the desiredamine.

Scheme 3—Route for Preferred Group 5 [4,5-g] Isomer

For the [4,5-g] isomer 7-chloroquinazol-4-one is nitrated at the6-position by methods familiar to one skilled in the art. The activated7-halide is then displaced by methoxide, the methyl ether is cleaved,the nitro group is reduced to amino, and the oxazole ring is cyclized onwith formic acid. Phosphorus pentasulflide followed by methyl iodideactivates the 4-position, and the synthesis is completed by displacementof the 4-methylthio group by an appropriate amine.

Scheme 4—Route for Preferred Group 5 [5,4-g] Isomer

For the [5,4-g] isomer the chlorine atom of the known5-chloro-2,4-dinitrobenzamide is displaced with KOH, and the two nitrogroups are then catalytically reduced to the diaminohydroxybenzamide.Treatment of this with excess orthoformate cyclizes both the oxazole andpyrimidone rings simultaneously, to give the desired tricyclic nucleus.Activation of the 4-oxo group with POCl₃ or other suitable chlorinatingagent followed by displacement with the appropriate amine gives thedesired compounds.

Scheme 5—Route for Preferred Group 6 [4,5-g] Isomer

For the [4,5-g] isomer 7-chloroquinazol-4-one is nitrated at the6-position by methods familiar to one skilled in the art. The activated7-halide is then displaced by methiolate ion, and the resultantthiomethyl ether is cleaved under the reaction conditions to give thecorresponding thiol. The nitro group is reduced by a noncatalyticmethod, such as treatment with hydrosulfide ion or Zn/AcOH, and thethiazole ring is cyclized on with orthoformate. Phosphorus pentasulfidefollowed by methyl iodide actvates the 4-position, and the synthesis iscompleted by displacement of the 4-methylthio group by an appropriateamine.

Scheme 6—Route for Preferred Group 6 [5,4-g] Isomer

For the [5,4-g] isomer the chlorine atom of the known5-chloro-2,4-dinitrobenzamide is displaced with NaSH, and the 4-nitrogroup is concomitantly reduced to give an aminonitrobenzamide disulfide.Treatment of this with borohydride, and then formic acid cyclizes thethiazole ring, to give the benzothiazole derivative. Reduction of thesecond nitro group followed by orthoformate cyclization gives thedesired tricyclic pyrimidone. Activation of the 4-oxo group with POCl₃or other suitable chlorinating agent followed by displacement with theappropriate amine gives the desired compounds.

Scheme 7—Route for Group 7

Nitration of 7-chloroquinazol-4-one at the 6-position by methodsfamiliar to one skilled in the art is followed by displacement of the7-chloro compound with ammonia. If a 3,N-alkyl substituent is required,an appropriate primary amine can be used instead of ammonia. Reductionwith Pearlman's catalyst gives 6,7-diaminoquinazolone which on treatmentwith formic acid cyclizes to the imidazoloquinazolone. Phosphoruspentasulfide followed by methyl iodide activates the 4-position, and thesynthesis is completed by displacement of the 4-methylthio group by anappropriate amine.

Scheme 8—Route to Preferred Group 10 [4,3-g] Isomers

2,4-Dimethylaniline is diazotized, and cyclized to a benzopyrazole.Nitration of this, followed by chromic acid oxidation and RaNi reductionof the nitro group gives the desired anthranilic acid derivative. Thisis cyclized to the pyrimidone with formamidine, and activated anddisplaced at the 4-position in the usual fashion.

Scheme 9—Route to Preferred Group 10 [3,4-g] Isomers

2,5-Dimethylacetanilide is nitrated, and the acetate group is saponifiedoff. Diazotization leads to the desired benzopyrazole, which in turn isoxidized to the corresponding benzoic acid derivative. Catalyticreduction of the nitro group with Pd/C is followed by formamidineacetate ring cyclization. The pyrimidone is activated to displacement inone of the usual fashions, and a suitable amine is then introduced atthe 4-position to give the desired compound.

Scheme 10—Route to Preferred Group 11 [4,5-g] Isomers

6,7-Diaminoquinazoline is prepared as described above in Scheme 7. Thiscompound can be cyclized to the triazoloquinazolone via a diazotization,and then the carbonyl is activated via phosphorus pentasulfide andmethyl iodide, as described previously and displaced with an appropriateamine to give the desired product.

Scheme 11—Route to Preferred Group 13 A & E Nitrogen

6,7-Diaminoquinazoline is prepared as described above. This compound canbe cyclized to a pyrazinoquinazolone by treatment with2,5-dihydroxy-1,4-dioxane, and then the carbonyl is activated viaphosphorus pentasulfide and methyl iodide, as described previously anddisplaced with an appropriate amine to give the desired product.

Scheme 12—Route to Preferred Group 13 B & E Nitrogen

Reaction of 1,3-diaminobenzene with chloral and hydroxylamine, followedby cyclization with conc. sulfuric acid gives the bis-isatin typetricycle. Oxidation with hydrogen peroxide gives the symmetricdiaminodiacid. This is doubly cyclized with formamidine, and convertedto the corresponding dichloride with POCl₃ or equivalent.Monodisplacement with the desired amine, can be followed by displacementof the remaining chloride hydrogenolytically or by a suitablenucleophile to put in R⁵.

Scheme 13—Route to Preferred Group 33 [4,5-f] Isomer

Nitration of 6-acetamidoquinazol-4-one gives the 5-nitro derivative.Hydrolysis of the amide with dilute HCl, followed by reduction withPearlman's catalyst gives the 5,6-diaminoquinazolone. Fusion of theimidazole ring by a formic acid gives the parent ring skeleton, and thenthe carbonyl is activated via phosphorus pentasulfide and methyl iodide,as described previously and displaced with an appropriate amine to givethe desired product.

Scheme 14—Route to Preferred Group 33 [4,5-h] Isomer

Nitration of 7-chloroquinazol-4-one by means obvious to one skilled inthe art gives the 8-nitro derivative as a minor product. This ispurified and the chlorine is displaced by ammonia under high temperatureand pressure to give the 5-amino compound which is then reduced byPearlman's catalyst (Pd hydroxide on carbon) to the7,8-diaminoquinazolone. Fusion of the imidazole ring by a formic acidderivative gives the parent ring skeleton, and then the carbonyl isactivated via phosphorus pentasulfide and methyl iodide, as describedpreviously and displaced with an appropriate amine to give the desiredproduct.

Scheme 15—Route to Preferred Group 39 [3.2-d] Isomer

2-Fluorobenzonitrile or a suitably substituted derivative of it istreated with ethyl thioglycollate and a base in a dipolar aproticsolvent to give an ethyl 3-aminobenzothiophene-2-carboxylate derivative.This is cyclized to the desired benzothienopyrimidone with formamide,and the carbonyl is replaced by chlorine using standard techniques, andthe chloride is displaced by an appropriate amine to give the desiredcompounds, or precursors that can readily be converted into them.

Scheme 16—Route to Preferred Group 39 [3,2-d] Isomer

In a variant of the route described in Scheme 15, lithia ion of asuitably substituted fluorobenzene ortho to the fluorine atom isfollowed by carbonylation. The aldehyde is converted onto a suitable2-fluorobenzonitrile derivative by oxime formation and dehydration.Alternatively the initial anion can be carboxylated and the resultingacid can be converted via the amide to the desired nitrile. This is thenput through the sequence described in Scheme 15, to prepare derivativeswhich could not be obtained by substitution on 2-fluorobenzonitrile.

Scheme 17—Route to Preferred Group 39 [2,3-d] Isomer

Commercially available 4,6-dichloropyrimidine can be monodisplaced with2-bromobenzenethiolate to give a diarylsulfide. This compound can bemetalated at the 5-position of the pyrimidine ring with LDA, andquenched with Me₃SnCl, to form a halostannane. This halostannane isintramolecularly Stille coupled to give the desired4-chlorobenzothieno[2,3-d]pyrimidine, from which chlorine can bedisplaced to give the desired product.

Scheme 18—Route to Preferred Group 41 [3′,2′:2,3] [4,5-d] Isomer

Halogen-metal exchange on 3-bromothiophene in ether at low temperature,followed by treatment with sulfur and then methyl bromoacetate givesmethyl (thien-3-ylthio)acetate. Vilsmeier formylation usingN-methylformanilide introduces a 2-formyl group on the thienyl ring,without inducing aldol cyclization. Reaction of the aldehyde to theoxime, followed by mesyl chloride/NEt₃ dehydration gives thecorresponding nitrile, which cyclizes to methyl3-aminothieno[3,2-b]thiophene-2-carboxylate on heating to 100° C. inDMSO with NEt₃. Pyrimidone fusion is carried out with formamide or anequivalent thereof, and the 4-keto substituent is activated anddisplaced in the usual manner to give the desired products.

Scheme 19—Route to Preferred Group 41 [2′,3′:2,3] [5,4-d] Isomer

Metalation of 3-bromothiophene with LDA occurs at the 2-position.Quenching of this anion with 1 equivalent of sulfur, followed by oneequivalent of 4,6-dichloropyrimidine gives the thienopyrimidosulfide.Selective metalation with LDA at the 5-position of the pyrimidine ring,followed by stannylation gives a precursor for Stille coupling. Afterthe coupling the 4-chlorine is displace with the appropriate amine togive the desired product.

Scheme 20—Route to Preferred Group 44 [4′,5′:2,3] [4.5-d] Isomer

Reaction of thiazolidin-2,4-dione with POCl₃ and DMF gives2,4-dichlorothiazole-5-carbaldehyde. Protection of the aldehyde as anacetal is followed by selective removal of the 2-chlorine byhalogen-metal exchange and hydrolysis. The aldehyde is oxidized up tothe corresponding nitrile by oxime formation and dehydration, and4-chloro-5-cyanothiazole on treatment with fresh 2-mercaptoacetamide inbasic conditions gives 6-aminothieno[2,3-d]thiazole-5-carboxamide. Thiscan be cyclized to the tricycle with ethyl orthoformate, and thecarbonyl replaced by POCl₃ in the usual manner, and the chloride is thendisplaced by a suitable amine to give the desired product.

Scheme 21—Route to Preferred Group 45 [4′,5′:2,3] [4,5-d] Isomer

1,N-Benzyl-4,5-dibromoimidazole is lithiated with butyl lithium andformylated with DMF. Reaction of the bromoaldehyde with ethylthioglycollate and base in DMSO leads to the desiredaminothienoimidazole. This in turn is annulated again with formamide oran equivalent thereof, and the tricyclic pyrimidone is chlorinated atthe 4-position and displaced with a suitable amine to give the desiredproduct.

Scheme 22—Route to Preferred Group 49 [2′,3′;2.3] [4.5-d] Isomer

Reaction of 2-chloronicotinonitrile with methyl thioglycollate givesmethyl 3-aminopyrido[2,3-d]thiophene-2-carboxylate. Fusion of thepyrimidone ring with formamide gives the corresponding pyrridothienopyrimidone, which can then be chlorinated on the carbonyl anddisplaced with appropriate amines in the usual fashion to yield thedesired compounds.

Scheme 23—Route to Preferred Group 50 [3,2-d] Isomer

A suitably substituted anthranilonitrile derivative is N-alkylated withethyl bromoacetate, and the pyrrole ring is closed by treating theproduct of that reaction with KOBu^(t), to give ethyl3-aminoindole-2-carboxylate. The pyrimidone ring is fused onto this withformamide, and the carbonyl converted to chloride with POCl₃.Displacement of the chlorine with a suitable amine gives the desiredcompound.

Scheme 24—Route to Preferred Group 50 [2,3-d] Isomer

The fluoride of 2-fluoronitrobenzene is displaced by the anion derivedfrom methyl cyanoacetate and KOBu^(t). Mild reduction of the nitro groupto amino is accompanied by spontaneous closure of the pyrrole ring togive ethyl 2-aminoindole-3-carboxylate. The pyrimidone ring is fusedonto this with formamide, and the carbonyl converted to chloride withPOCl₃. Displacement of the chlorine with a suitable amine gives thedesired compound.

Scheme 25—Route to Preferred Group 61 [3,2-d] Isomer

O-Alkylation of 2-cyanophenol with methylbromoacetate, followed bytreatment with a strong base gives ethyl3-aminobenzofuran-2-carboxylate. The pyrimidone ring is fused onto thiswith formamide, and the carbonyl converted to chloride with Vilsmeierreagent. Displacement of the chlorine with a suitable amine gives thedesired compound.

Biology

These compounds are potent and selective inhibitors of the human EGFreceptor tyrosine kinase, and other members of the EGF receptor family,including the ERB-B2, ERB-B3 and ERB-B4 receptor kinases, and are usefulfor the treatment of proliferative diseases in mammals. These inhibitorsprevent mitogenesis in cells where mitogenesis is driven by one or moreof this family of receptor kinases. This can include normal cells, whereit is desired to prevent mitogenesis, as exemplified by the cellstransformed by overexpression or mutation of this kinase family asexemplified by poor prognosis breast cancer where overexpression ofEGFR, ERB-B2 and ERB-B3 or mutation of ERB-B2 to the oncoprotein NEU isa major factor in cellular transformation. As the preferred compoundsare not highly cytotoxic and do not show potent growth inhibitoryproperties, because of their high specificity toward inhibition of theEGFR kinase family, they should have a much cleaner toxicity profilethan most anti-cancer and anti-proliferative drugs. Their very differentmode of action to current anti-cancer drugs should allow for their usein multiple drug therapies, where synergism with available agents isanticipated.

Compounds of the invention have been shown to be very potent, reversibleinhibitors of the EGF receptor tyrosine kinase, by binding with highaffinity at the adenosine triphosphate (ATP) binding site of the kinase.These compounds exhibit potent IC₅₀s, varying from 10 micromolar to 50picomolar, for the tyrosine kinase activity of the enzyme, based on anassay examining phosphorylation of a peptide derived from thephosphorylation site of the protein PLCgammal, a known EGFRphosphorylation substrate. This data is shown in Table 1.

Biological Data

Materials and Methods

Purification of Epidermal Growth Factor Receptor Tyrosine Kinase—HumanEGF receptor tyrosine kinase was isolated from A431 human epidermoidcarcinoma cells which overexpress EGF receptor by the following methods.Cells were grown in roller bottles in 50% Delbuco's Modified Eagle and50% HAM F-12 nutrient media (Gibco) containing 10% fetal calf serum.Approximately 10⁹ cells were lysed in two volumes of buffer containing20 mM 2-(4N-[2-hydroxyethyl]piperazin-1-yl)ethanesulfonic acid (hepes),pH 7.4, 5 mM ethylene glycol bis(2-aminoethyl ether)N,N,N′,N′-tetraacetic acid, 1% Triton X-100, 10% glycerol, 0.1 mM sodiumorthovanadate, 5 mM sodium fluoride, 4 mM pyrophosphate, 4 mM benzamide,1 mM dithiothreitol, 80 μg/mL aprotinin, 40 μg/mL leupeptin and 1 mMphenylmethylsulfonyl fluoride. After centrifugation at 25,000×g for 10minutes, the supernatant was equilibrated for 2 h at 4° C. with 10 mL ofwheat germ agglutinin sepharose that was previously equilibrated with 50mM Hepes, 10% glycerol, 0.1% Triton X-100 and 150 mM NaCl, pH 7.5,(equilibration buffer). Contaminating proteins were washed from theresin with 1 M NaCl in equilibration buffer, and the enzyme was elutedwith 0.5 M N-acetyl-1-D-glucosamine in equilibration buffer, followed by1 mM urea. The enzyme was eluted with 0.1 mg/ml EGF. The receptorappeared to be homogeneous as assessed by Coomassie blue stainedpolyacrylamide electrophoretic gels.

Determination of IC₅₀ values—enzyme assays for IC₅₀ determinations wereperformed in a total volume of 0.1 mL, containing 25 mM Hepes, pH 7.4, 5mM MgCl₂, 2 mM MnCl₂, 50 μM sodium vanadate, 5-10 ng of EGF receptortyrosine kinase, 200 μM of a substrate peptide,(Ac-Lys-His-Lys-Lys-Leu-Ala-Glu-Gly-Ser-Ala-Tyr⁴⁷²-Glu-Glu-Val-NH₂,derived from the amino acid (Tyr⁴⁷² has beer shown to be one of fourtyrosines in PLC (phospholipaseC)-gamma 1 that are phosphorylated by theEGF receptor tyrosine kinase [Wahl, M. I.; Nishibe, S.; Kim, J. W.; Kim,H.; Rhee, S. G.; carpenter, G., J. Biol. Chem., (1990), 265,3944-3948.], and peptides derived from the enzyme sequence surroundingthis site are excellent substrates for the enzyme.),10 μM ATP containing1 μCi of [³²P]ATP and incubated for ten minutes at room temperature. Thereaction was terminated by the addition of 2 mL of 75 mM phosphoric acidand passed through a 2.5 cm phosphocellulose filter disc to bind thepeptide. The filter was washed five times with 75 mM phosphoric acid andplaced in a vial along with 5 mL of scintillation fluid (Ready gelBeckman).

TABLE 1 EGF Receptor Tyrosine Kinase Inhibition Example # IC₅₀ in EGFR 1<100 pM 2 21 nM 3 760 pM 4 44 nM 5 75 pM 6 6 pM 7 4.1 nM 8 30 pM 9 ˜10pM 10 1.7 nM 11 272 nM 12 29 nM 13 191 nM 14 538 nM 15 1.8 nM 16 12.3 nM17 270 pM 18 36% @ 10 nM 19 40 nM 20 1.3 μM 21 732 nM 22 2.11 μM 23 460nM 24 419 nM 25 72 nM 26 132 nM 27 264 nM 28 31 nM 29 732 nM 30 4.1 μM31 220 nM 32 160 nM 33 34 740 nM

Cells

Swiss 3T3 mouse fibroblasts, A431 human epidermoid carcinoma cells, andMCF-7 (Michigan Cancer Foundation human mammary carcinoma cells),SK-BR-3 (human mammary carcinoma cells), MDA-MB-231 and MDA-MB-468(human mammary carcinoma cells) breast carcinomas were obtained from theAmerican Type Culture Collection, Rockville, Md. and maintained asmonolayers in DMEM (Dulbecco's modified eagle medium)/F12, 50:50(Gibco/BRL) containing 10% fetal bovine serum. To obtain conditionedmedium, MDA-MB-231 cells were grown to confluency in an 850 cm² rollerbottle and the medium replaced with 50 ml of serum-free medium. After 3days the conditioned medium was removed, frozen down in aliquots andused as a heregulin source to stimulate erbB-2, 3, 4.

Antibodies

Monoclonal antibodies raised to phosphotyrosine were obtained fromUpstate Biotechnology, Inc., Lake Placid, N.Y. Anti-EGF receptorantibodies were obtained from Oncogene Science, Uniondale, N.Y.

Immunoprecipitation and Western Blot

Cells were grown to 100% confluency in 100 mm Petrie dishes (Corning).After the cells were treated for 5 minutes with either EGF (epidermalgrowth factor), PDGF, or bFGF (basic fibroblast growth factor) (20ng/ml) or 1 ml of conditioned media from MDA-MB-231 cells, the media wasremoved and the monolayer scraped into 1 ml of ice cold lysis buffer (50mM Hepes, pH 7.5, 150 mM NaCl, 10% glycerol, 1% triton X-100, 1 mM EDTA,1 mM EGTA, 10 mM sodium pyrophosphate, 30 mM p-nitrophenyl phosphate, 1mM orthovanadate, 50 mM sodium fluoride, 1 mMphenylmethylsulfonylfluoride, 10 μg/ml of aprotinin, and 10 μg/ml ofleupeptin). The lysate was transferred to a microfuge tube (smallcentrifuge that holds 1-2 ml plastic centrifuge tubes), allowed to siton ice 15 minutes and centrifuged 5 minutes at 10,000×g. The supernatantwas transferred to a clean microfuge tube and 5 μg of antibody was addedto designated samples. The tubes were rotated for 2 hours at 4° C. afterwhich 25 μl of protein A sepharose was added and then rotation continuedfor at least 2 more hours. The protein A separose was washed 5 timeswith 50 mM Hepes, pH 7.5, 150 mM NaCl, 10% glycerol and 0.02% sodiumazide. The precipitates were resuspended with 30 μl of Laemlli buffer(Laemmli, NATURE, Vol. 727, pp. 680-685, 1970), heated to 100° C. for 5minutes and centrifuged to obtain the supernatant. Whole cell extractswere made by scraping cells grown in the wells of 6 well plates into 0.2ml of boiling Laemmli buffer. The extract were transferred to amicrofuge tube and heated to 100° C. for 5 minutes. The entiresupernatant from the immunoprecipitation or 35 μl of the whole cellextract was loaded onto a polyacrylamide gel (4-20%) and electrophoresiscarried out by the method of Laemlli (Laemmli, 1970). Proteins in thegel were electrophoretically transferred to nitrocellulose and themembrane was washed once in 10 mM Tris buffer, pH 7.2, 150 mM NaCl,0.01% Azide (TNA) and blocked overnight in TNA containing 5% bovineserum albumin and 1% ovalbumin (blocking buffer). The membrane wasblotted for 2 hours with the primary antibody (1 μg/ml in blockingbuffer) and then washed 2 times sequentially in TNA, TNA containing0.05% Tween-20 and 0.05% Nonidet P-40 (commercially available detergent)and TNA. The membranes were then incubated for 2 hours in blockingbuffer containing 0.1 μCi/ml of [¹²⁵I] protein A and then washed againas above. After the blots were dry they were loaded into a film cassetteand exposed to X-AR X-ray film for 1-7 days. Protein A is a bacterialprotein that specifically bonds certain IgG subtypes and is useful inbinding to and isolating antibody-antigen complexes.

Growth Inhibition Assay

Cells (2×10⁴) were seeded in 24-well plates (1.7×1.6 cm, flat bottom) intwo mls of medium with or without various concentrations of drug. Plateswere incubated for 3 days at 37° in a humidified atmosphere containing5% CO₂ in air. Cell growth was determined by cell count with a CoulterModel AM electronic cell counter (Coulter Electronics, Inc., Hialeah,Fla.).

Inhibition of EGF-Induced Autophosphorylation in A431 EpidermoidCarcinoma Cells and Conditioned Media-Induced Autophosphorylation inSK-BR-3 Breast Tumor Cells by Compounds of the Current Invention

Example # EGFR IC₅₀ nM A431 IC₅₀ nM SKBR-3 IC₅₀ nM 1 <0.1 17 ND 6 0.00846 55 8 0.03 26 10 10 1.7 31 ˜700 15 1.8 170 ND 17 0.27 86 23 19 40 ND˜1500 25 72 93 1000 28 31 630 10 29 732 109 1100

The gels shown in the drawings, developed as detailed in theexperimental section, demonstrate the efficacy of compounds of thecurrent invention at blocking certain EGF-stimulated mitogenicsignalling events in whole cells. The numbers to the left of gelsindicate the positions of molecular weight standards in kiloDaltons. Thelane labelled control shows the degree of expression of thegrowth-related signal in the absence of EGF stimulation, whereas thelane labelled EGF (or PDGF or b-FGF) shows the magnitude of the growthfactor-stimulated signal. The other lanes show the effect of the statedquantities of the named drug on the growth factor-stimulated activitybeing measured, demonstrating that the compounds of the presentinvention have potent effects in whole cells, consistent with theirability to inhibit the tyrosine kinase activity of the EGF receptor.

See also the results as shown in FIGS. 1-8.

Antiproliferative Properties of Tyrosine Kinase Inhibitors IC₅₀ (nM)

Example 6 Example 17 B104-1-1 3200 2900 SK-BR-3 200 1800 MDA-468 200001800

B104-1-1—NIH-3T3 mouse fibroblasts transfected by the neu oncogene:Stern et al., Science, 234, pp. 321-324 (1987);

SK-BR-3—Human breast carcinoma overexpressing erbB-2 and erbB-3;

MDA-468—Human breast carcinoma overexpressing the EGF receptor.

Soft Agar Clonogenic Assays

Cell monolayers were exposed to the appropriate compound for 1-3 daysand were then washed free of drug with warmed serum-free media. Thecells were trypsinised and 10,000/mL were seeded into DMEM/F12 mediacontaining 10% fetal calf serum and 0.4% agarose, but no drug. One ml ofthis solution was placed over a bottom layer of the same mediumcontaining 0.8% agarose in a 35 mm Petri dish, and was incubated at 37°C. in a humidified atmosphere containing 5% carbon dioxide in air. After3 weeks colonies were counted using an image analyzer forquantification. See FIG. 9.

It is to be appreciated that the compounds described herein can be usedin combination with other components to enhance their activity. Suchadditional components are anti-neoplastic materials as, doxorubicin,taxol, cis platin, and the like.

It has been found that the compounds described herein may inhibit boththe erb-B2 and erb-B4 receptors and therefore have significantlyincreased clinical activity advantageously in combination with theaforementioned anti-neoplastic agents.

See J. Basalga et al., Antitumor Effects of Doxorubicin in CombinationWith Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies. JNCI,1993, 85 1327, and Z. Fan et al., Antitumor Effect of Anti-EpidermalGrowth Factor Receptor Monoclonal Antibodies Plus CisDiamminedichloroplatinum on Well Established A431 Cell Xenografts.Cancer Res. 1993, 53, 4637.

Chemical Experimental

Listed below are preferred embodiments wherein all temperatures are indegrees Centigrade and all parts are parts by weight unless otherwiseindicated.

EXAMPLE 1 4-(3-bromoanilino)benzo[q]quinazoline hydrochloride

3H-Benzo[g]quinazol-4-one. 3-Amino-2-naphthoic acid (3.74 g, 20 mmol) instirred formamide is heated under N2 to 135° C. for 30 min, and to 175°C. for 2 h. The reaction mixture is poured onto vigorously stirreddilute NaOH solution (0.2 M, 50 is mL), containing ice, and the solid iscollected by vacuum filtration, rinsed with water (2×25 mL), and driedin a vacuum oven at 60° C. to give benzo[g]-3H-quinazol-4-one (3.49 g,89%) as a pale khaki solid. ¹H NMR (DMSO) δ12.08 (1H, brs), 8.84 (1H,s), 8.24 (1H, s), 8.21 (1H, d, J=7 Hz), 8.10 (1H, d, J=7 Hz), 8.09 (1H,s), 7.62 (2H, apparent d of pentets, J_(d)=1.3 Hz, J_(p)=6.7 Hz).

4-Chlorobenzo[g]quinazoline. A suspension of benzo[g]-3H-quinazol-4-one(3.49 g, 18 mmol) in POCl₃ (40 mL) was refluxed under N₂ for 3 h. Thevolatiles were removed under reduced pressure, and the residue waspartitioned between chloroform (200 mL) and dilute aqueous Na₂HPO₄solution (1 M, 50 mL). The organic phase was filtered through a silicagel plug (50 g), and the plug was then eluted with 20% EtOAc in CHCl₃(500 mL). The combined eluents were concentrated under reduced pressureto give 4-chlorobenzo[g]quinazoline (1.20 g, 31%) as an orange-yellowsolid. ¹H NMR (DMSO) δ9.04 (1H, s), 8.91 (1H, s), 8.65 (1H, s),8.20-8.09 (2H, m), 7.75-7.60 (2H, m).

4-(3-Bromoanilino)benzo[g]quinazoline hydrochloride.4-Chlorobenzo[g]quinazoline (214 mg, 1.0 mmol), 3-bromoaniline (213 mg,1.25 mmol) and NEt₃ (202 mg, 2.0 mmol) in stirred methoxyethanol (5 mL)were heated under N₂ at 95° C. for 6 h. The volatiles were removed underreduced pressure and the residual solid was triturated with MeOH. Thesolid was recrystallized at 0° C. from an EtOHt dilute hydrochloric acidmixture (1:4, 0.05 M acid, 50 mL) after celite filtration to give4-(3-bromoanilino)-benzo[g]quinazoline hydrochloride (71 mg, 18%) as ayellow-green solid. ¹H NMR (DMSO) δ14.0 (1H brs), 9.65 (1H, s), 9.01(1H, s), 8.47 (1H, s), 8.29 (1H, d, J=8.4 Hz), 8.24 (1H, d, J=8.4 Hz),8.18 (1H, slbrs), 7.9-7.82 (2H, m), 7.78 (1H, t, J=7.5 Hz), 7.58 (1H, d,J=8 Hz), 7.51 (1H, t, J=8 Hz).

EXAMPLE 2 4-([R]-1-Phenylethylamino)benzo[g]quinazoline hydrochloride

4-Chlorobenzo[g]quinazoline (107 mg, 0.5 mmol), [R]-1-phenylethylamine(72 mg, 0.6 mmol) and NEt₃ (202 mg, 2.0 mmol) in stirred methoxyethanol(2 mL) are heated under N₂ at 100° C. for 90 min. On cooling thereaction mixture is diluted with CHCl₃ (10 ML), and is shaken withdilute hydrochloric acid (0.2 M, 15 mL). The heavy yellow precipitate iscollected by Buchner filtration, rinsed with water (5 mL), and dried invacuo at 60° C. to give 4-([R]-1-phenylethyl-amino)benzo[g]quinazolinehydrochloride hydrate (122 mg, 64%) as a yellow solid. ¹H NMR (DMSO)δ14.75 (1H brs), 10.85 (1H, d, J=8.0 Hz), 9.61 (1H, s), 8.90 (1H, s),8.36 (1H, s), 8.18 (1H, d, J=8.2 Hz), 7.82 (1H, t, J=7.6 Hz), 7.74 (1H,t, J=7.4 Hz), 7.56 (2H, d, J=7.5 KHz), 7.39 (2H, t, J=7.6 Hz), 7.30 (1H,t, J=7.4 Hz), 5.92 (1H, pentet, J=7.2 Hz), 1.76 (3H, d, J=7.2 Hz).

EXAMPLE 3 4-(3-Bromoanilino)pyrrolo[3,2-g]quinazoline

N-(5-(E,2-dimethylaminoethtenyl)-2,4-dinitrobenzoyl)-N′N′-dimethylformamidine.To a solution of 5-methyl-2,4-dinitrobenzamide (Blatt, A. H. J. Org.Chem 1960, 25, 2030.) (2.25 g, 10 mmol) in DMF (10 mL) is addedt-butoxy-bis(dimethylamino)methane (6.2 mL, 30 mL). The reaction mixtureis stirred at 55° C. for 2 h. The solvent is evaporated under reducedpressure and the residue is suspended in water. The precipitate isfiltered and washed with water and ethyl ether to giveN-(5-(E,2-dimethylaminoethtenyl)-2,4-dinitrobenzoyl)-N′N′-dimethylformamidine,2.76 g (84%). ¹H NMR (DMSO) δ8.55 (1H, s), 8.47 (1H, s),8.04 (1H, d,J=13.0 Hz), 7.76 (1H, s), 5.95 (1H, d, J=13.0 Hz), 3.21 (3H, s), 3.00(9H, m).

4-Oxo-3H-pyrroloquinazoline. A mixture ofN-(5-(E,2-dimethylaminoethtenyl)-2,4-dinitrobenzoyl)-N′N′-dimethylformamidine(600 mg, 1.79 mmol) and Raney nickel (200 mg) in THF-MeOH (25:25 mL) ishydrogenated in a rocking autoclave at 1500 psi at room temperature for22 h. The catalyst is filtered off and the filtrate is concentrated invacuo. The crude product is triturated in isopropanol and filtered. Thesolid is then washed with isopropanol and ethyl ether and dried in avacuum oven at 40° C. to give 4-oxo-3H-pyrroloquinazoline(190 mg, 58%)as a bright red solid

¹H NMR (DMSO) δ11.8 (1H, brs), 11.6 (1H, brs,) 8.43 (1H, s), 7.95 (1H,s, J=3.1 Hz), 7.73 (1H, d, J=3.4 Hz), 7.55 (1H, s), 6.58 (1H, d, J=3.4Hz).

4-(3-Bromoanilino)pyrrolo[3,2-g]quinazoline. 4-Oxo-3H-pyrroloquinazoline(100 mg, 0.54 mmol) in POCl₃ (5 mL) is refluxed under N₂ for 20 h. Theresulting dark red solution is cooled to room temperature and extractedwith ethyl acetate (2×20 mL). The organic layer is dried (Na₂SO₄) andconcentrated to give a red solid (30 mg). Without further purification,this is suspended in 2-propanol (2 mL) containing m-bromoaniline (0.1mL, 0.8 mmol). The reaction mixture is then refluxed for 1 h. Theresulting bright yellow precipitate is filtered and washed with waterand ether to yield 4-(3-bromoanilino)pyrrolo-[3,2-g]quinazoline(15 mg,8%). ¹H NMR (DMSO) δ11.7 (1H, brs), 10.5 (1H, brs), 8.89 (1H, s), 8.73(1H, brs), 8.16 (1H, s), 7.80 (3H, m), 7.35 (2H, s), 6.77 (1H, s).

EXAMPLE 4 4-(3-Bromoanilino)thiazolo[5,4-g]quinazoline

5,5′-Dithiobis(4-amino-2-nitrobenzamide). A solution of NaSH in aqueousMeOH (prepared according to Vogel, in “Elementary Practical OrganicChemistry, Part 1”) is added dropwise with stirring to a solution of5-chloro-2,4-dinitrobenzamide (5.00 g, 0.020 mmol) in a mixture ofTHF/MeOH (1:1, 200 mL) until no further reaction is observed (TLCanalysis). The solution is then diluted with water and washed withCH₂Cl₂. The aqueous portion is acidified with concentrated HCl,extracted with EtOAc, and the extract is worked up to give an oily solidwhich is stirred vigorously with MeOH for 3 h. The resultant precipitateis removed by filtration to give5,5′-dithiobis(4-amino-2-nitrobenzarride) (3.11 g, 64%) as a tan powder.¹H NMR (DMSO) δ8.88 (1H, brs), 8.33 (1H, brs), 7.99 (1H, s), 7.94 (1H,s), 3.6-3.3 (2H, brs).

5-Nitrobenzothiazole-6-carboxamide. NaBH₄ (0.50 g, 0.013 mmol) is addedto a vigorously stirred suspension of5,5′-dithiobis(4-amino-2-nitrobenzamide) (3.00 g, 7.13 mmol) in MeOH (60mL). After 10 min the solution is acidified with concentrated HCl,extracted with EtOAc, and worked up rapidly to give4-amino-5-mercapto-2-nitrobenzamide as an unstable solid which is useddirectly. The crude material is dissolved in formic acid (50 mL) heatedunder gentle reflux for 2 h, and then concentrated to dryness. Theresidue is triturated with MeOH/EtOAc (1:19), and unreacted disulfide(1.41 g) is recovered by filtration. The filtrate is concentrated andchromatographed on silica. Elution with EtoAc/petroleum ether (4:1)gives foreruns, while EtOAc gives 5-nitrobenzothiazole-6-carboxamide(1.31 g, 41%) as a yellow powder. ¹H NMR (DMSO) δ9.70 (1H, s), 8.71 (1H,s), 8.52 (1H, s), 8.25 (1H, brs), 7.78 (1H, brs).

Thiazolo[5,4-g]quinazol-4(3H)-one. A solution of5-nitrobenzothiazole-6-carboxamide (0.30 g, 1.34 mmol) in MeOH/EtOAc(1:1, 25 mL) is hydrogenated over 5% Pd/C at 60 psi for 1 h to give5-aminobenzothiazole-6-carboxamide. This is immediately dissolved intriethyl orthoformate (30 mL) and the mixture is heated under gentlereflux for 18 h. An equal volume of petroleum ether is added to thecooled solution, precipitating thiazolo[5,4-g]quinazol-4(3H)-one (0.17g, 57%) as a tan powder. ¹H NMR (DMSO) δ12.30 (1H, brs), 9.67 (1H, s).9.00 (1H, s), 8.31 (1H, s), 8.14 (1H, s).

4-(3-Bromoanilino)thiazolo[5,4-g]quinazoline. A suspension of thethiazolo[5,4-g]quinazol-4(3H)-one (0.25 g, 1.23 mmol) in POCl₃ (20 mL)is heated under reflux for 3 h, then concentrated to dryness. Theresidue is partitioned between saturated aqueous NaHCO₃ and EtOAc, andthe organic portion is worked up to give4-chlorothiazolo[4,5-g]quinazoline (0.21 g, 0.95 mmol) as a yellow solidwhich is used directly. The crude product and 3-bromoaniline (0.21 mL,1.90 mmol) are heated under reflux for 45 min in THF/propan-2-ol (1:1,20 mL) containing a trace of concentrated HCl, and then concentrated todryness. After trituration with EtOAc, the residue is partitionedbetween saturated aqueous NaHCO₃ and EtOAc and the organic portion isworked up to give 4-(3-bromoanilino)thiazolo[5,4-g]quinazoline (0.19 g,49%), . ¹H NMR (DMSO) δ10.05 (1H, brs), 9.74 (1H, s), 9.38 (1H, s), 8.71(1H, s), 8.48 (1H, s), 8.31 (1H, brs), 7.96 (1H, d, J=7.7 Hz), 7.39 (1H,t, J=7.7 Hz,), 7.33 (1H,d, J=7.7 Hz).

EXAMPLE 5 4-(3-Bromoanilino)oxazolo[5,4-g]quinazoline

2,4-Dinitro-5-hydroxybenzamide. A solution of5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol) in p-dioxane/methanol(1:1, 120 mL) and 6N aqueous KOH (20 mL) is stirred at room temperaturefor 2 h. After acidification with concentrated HCl, the mixture isdiluted with water and extracted into EtOAc. Workup gives2,4-dinitro-5-hydroxybenzamide (4.91 g, 98%) as yellow cubes. ¹H NMR(DMSO) δ8.64 (1H, s), 8.16 (1H, brs), 7.81 (1H, brs), 7.13 (1H, s), 5.80(1H, brs).

4-Oxo-3H-oxazolo[5,4-g]quinazoline. A solution of2,4-dinitro-5-hydroxybenzamide (4.00 g, 0.018 mmol) in MeOH/EtOAc (1:1,50 mL) is hydrogenated over 5% Pd/C at 60 psi for 3 h to give2,4-diamino-5-hydroxybenzamide, which is used directly. Formic acid (50mL) is added and the solution is heated under reflux for 48 h. then thevolatiles are removed under reduced pressure. The residue is trituratedwith EtOAc to give crude 4-oxo-3H-oxazolo[5,4-g]quinazoline (3.27 g,97%) as a tan powder which is used directly.

4-Chlorooxazolo[5,4-g]quinazoline. A suspension of4-oxo-3H-oxazolo[5,4-g]quinazoline (0.98 g, 5.24 mmol) in POCl₃ (30 mL)is heated under reflux with vigorous stirring for 18 h, and thenconcentrated to dryness. The residue is partitioned between EtOAc andsaturated aqueous NaHCO₃ and the organic portion is worked up to give4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 22%) as a yellow solid whichis used directly.

4-(3-Bromoanilino)oxazolo[5,4-g]quinazoline. A mixture of4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 1.16 mmol) and 3-bromoaniline(0.25 mL, 2.33 mmol) in a THF/propan-2-ol mixture (1:1, 40 mL)containing a trace of concentrated HCl is heated under reflux for 15min, then concentration to dryness under reduced pressure. The residueis triturated with EtOAc, and then partitioned between saturated aqueousNaHCO₃ and EtOAc. Workup of the organic portion gives4-(3-bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%) as a yellowpowder, mp (MeOH) 232° C. (dec.).

EXAMPLE 6 4-(3-Bromoanilino)imidazolo[4,5-g]quinazoline

A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.5 g, 1.6 mmol)[Leonard, N. J.; Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975,40, 356-363], 3-bromoaniline (0.35 g, 2.0 mmol), and 3-bromoanilinehydrochloride (0.4 g, 1.9 mmol) in isopropanol (200 mL) is heated underreflux for 1 h to give a precipitate of4-(3-bromoanilino)-6H-imidazo[4,5-g]quinazoline hydrochloride (0.63 g,72 %). ¹H NMR (DMSO) δ9.93 (1H, brs), 9.01 (1H, s), 8.66 (2H, s), 8.39(1H, s), 8.04 (2H, m), 7.39 (1H, t, J=7.9 Hz), 7.31 (1H, brd, J=8.0 Hz).

EXAMPLE 7 4-(3-Bromoanilino)triazolo[4,5-g]quinazoline hydrochloride

4-Oxo-3H-triazolo[4,5-g]quinazoline. A solution of6,7-diamino-4-oxo-3H-quinazoline (91 g, 5.7 mmol) [Leonard, N. J.;Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363] in0.1 M HCl (250 mL) is cooled to below 10° C., and a solution of NaNO₂(0.41 g, 6 mmol) in water (10 mL) is added over 2 min. After 15 min thesolution is neutralized with 0.1 M KOH solution to give a precipitate of4-oxo-3H-triazolo[4,5-g]quinazoline (1.01 g, 94%). ¹H NMR (DMSO) δ12.22(2H, m), 8.76 (1H, s), 8.12 (1H, s), 8.07 (1H, s).

4-Thiono-3H-triazolo[4,5-g]quinazoline. A mixture of4-oxo-3H-triazolo[4,5-g]quinazoline (0.56 g, 3 mmol) and P₂S₅ (1.3 g, 6mmol) in pyridine (20 mL) is heated under reflux for 2 h, and thesolvent is removed under reduced pressure. The residue is treated withboiling water (30 mL) to give a yellow solid which is collected byfiltration and dissolved in 0.1 M KOH solution. After filtration toremove insolubles, the clear yellow solution is neutralized with diluteHCl to give 4-thiono-3H-triazolo[4,5-g]quinazoline (0.26 g, 43%). 1H NMR(DMSO) δ9.20 (1H, s), 8.15 (1H, s), 8.14 (1H, s).

4-Methylthiotriazolo[4,5-g]quinazoline. A solution of4-thiono-3H-triazolo[4,5-g]quinazoline (0.203 g, 1 mmol) and KOH (0.15g, 2.7 mmol) in 50% MeOH-H₂O (15 mL) is treated with MeI (65 μL, 1.0mmol) and the mixture is stirred at room temperature overnight. The MeOHis removed under vacuum and the solution neutralized with dilute HCl togive crude 4-methylthiotriazolo[4,5-g]quinazoline (0.12 g, 55%). ¹H NMR(DMSO) δ8.96 (1H, s), 8.79, (1H, s), 8.40 (1H, s), 2.74 (3H, s).

4-(3-Bromoanilino)-triazolo[4,5-g]quinazoline hydrochloride. A mixtureof 4-methylthiotriazolo[4,5-g]quinazoline (0.30 g, 1.38 mmol),3-bromoaniline (2.1 mmol) and 3-bromoaniline hydrochloride (2.1 mmol) inisopropanol (400 mL) is heated under reflux for 6 h, and the solution isconcentrated to give 4-(3-bromoanilino)-triazolo[4,5-g]quinazolinehydrochloride (0.33 g, 63%). ¹H NMR (DMSO) δ12.01 (1H, brs), 9.86 (1H,s), 9.02 (1H, s), 8.63 (1H, s), 8.39 (1H, s), 8.13 (1H, dd, J=1.9, 1.5Hz), 7.85 (1H, ddd, J=7.7, 1.9, 1.5 Hz), 7.56 (1H, ddd, J=8.0, 1.7, 1.5Hz), 7.41 (1H t, J=7.8 Hz).

EXAMPLE 8 4-(3-Bromoanilino)-8,N-methylimidazolo[4,5-g]quinazoline

8,N-Methyl-3H-imidazo[4,5-g]quinazolin-4-thione. A mixture of of8,N-methyl-3H-imidazo[4,5-g]quinazolin-4-one (2.32 g, 11.1 mmol) [Lee,C.-H.; Gilchrist, J. H.; Skibo, E. B.; J. Org. Chem., 1986, 51,4784-4792] and P₂S₅ (3.96 g, 17.8 mmol) in pyridine (25 mL) is heatedunder reflux for 16 h. The pyridine is removed under vacuum, and theresidue is treated with boiling water (50 mL). The precipitate iscollected, washed with water, and dissolved in 0.1 M KOH. Afterfiltration to remove insolubles, the clear yellow solution is acidifiedwith AcOH to give 8,N-methyl-3H-imidazo[4,5-g]quinazoline-4-thione (2.12g, 88%). ¹H NMR (DMSO) δ8.91 (1H, s), 8.53 (1H, s), 8.12 (1H, s) 7.91(1H, s), 3.93 (3H,s).

8,N-Methyl-4-methylthioimidazo[4,5-q]quinazoline. MeI (0.61 ml, 9.5mmol) is added to a solution of8,N-methyl-3H-imidazo[4,5-g]quinazoline-4-thione(1.87 g, 8.65 mmol) andKOH (0.58 g, 10 mmol) in 100 ml 50% MeOH-H₂O, and the resulting mixtureis stirred at room temperature for 30 min. The precipitated product isfiltered off, and dried, to give8,N-methyl-4-methylthioimidazo[4,5-g]quinazoline (1.89 g, 82%). ¹H NMR(DMSO) δ8.96 (1H, s), 8.64 (1H, s), 8.39 (1H, s), 8.16 (1H, s), 3.98(3H, s), 2.74 (3H, s).

4-(3-Bromoanilino)-8,N-methylimidazolo[4,5-g]quinazoline. A mixture of8,N-methyl-4-methylthioimidazo[4,5-g]quinazoline (1.50 g, 6.5 mmol),3-bromoaniline (1.7 g, 10 mmol), and 3-bromoaniline hydrochloride (2.1g, 10 mmol) in isopropanol (400 mL) is heated under reflux for 4 h togive a precipitate of the product hydrochloride, which is treated withaqueous NH₃ to give4-(3-bromoanilino)-8,N-methylimidazo[4,5-g]quinazoline (1.22 g, 52%).NMR (DMSO) δ9.86 (1H, s), 9.02 (1H, s), 8.63 (1H, s), 8.54 (1H, s), 8.37(1H, s), 8.01 (2H, m), 7.36 (1H, t, J=8.0 Hz), 7.28 (1H, brd), 3.96 (3H,s).

EXAMPLE 9 4-(3-Bromoanilino)-6,N-methylimidazolo[4,5-g]quinazoline

2,4-Dinitro-5-methylaminobenzamide. A solution of5-chloro-2,4-dinitrobenzamide (6.14 g, 25 mmol) [Goldstein, H.; Stamm,R.; Helv. Chim. Acta, 1952, 35, 1330-1333] and 40% aqueous methylamine(20 mL) in ethanol (80 mL) is heated in a sealed pressure vessel at 100°C. for 2 h. After cooling, dilution with water gives2,4-dinitro-5-methylaminobenzamide (5.89 g, 98%). ¹H NMR (DMSO) δ8.88(1H, q, J=4.9 Hz), 8.76 (1H, s), 8.07 (1H, brs), 7.77 (1H, brs), 6.98(1H,s), 3.07 (3H, d, J=5.0 Hz).

6,N-methyl-3H-imidazo[4,5-g]quinazolin-4-one. A suspension of2,4-dinitro-5-methylaminobenzamide(4.80 g, 20 mmol) in ethanol andformic acid (2.5 mL, 66 mmol) is hydrogenated over 5% Pd/C, and thesolvent is removed under reduced pressure. The resulting crude salt isdissolved in formic acid (100 mL) and the mixture is heated under refluxfor 2 h. The formic acid is removed under reduced pressure, and theresidue is dissolved in the minimum volume of 0.1 M HCl. Afterclarification with charcoal and filtration through celite, the aqueoussolution is neutralized with dilute aqueous NH₃, and allowed to standovernight, to give 6,N-methyl-3H-imidazo[4,5-g]quinazolin-4-one (2.99 g,75%). ¹H NMR (DMSO) δ11:91 (12H, brs), 8.50 (1H, s), 8.33 (1H, s), 8.00(1H, s), 7.89 (1H, s), 3.95 (3H, s).

6,N-Methyl-3H-imidazo[4,5-g]quinazolin-4-thione. A mixture of6,N-methyl-3H-imidazo[4,5-g]quinazolin-4-one (2.50 g, 12.5 mmol) andP₂S₅ (5.55 g, 25 mmol) in pyridine (30 mL) is heated under reflux for 16h, and the pyridine is removed under reduced pressure. The residue istreated with boiling water (50 mL), and the resulting yellow precipitateis collected by filtration and dissolved in 0.1 M KOH solution. Afterfiltration to remove insolubles, the solution is neutralized with NH₄Clto give 6,N-methyl-3H-imidazo[4,5-g]quinazolin-4-thione (1.58 g, 59%).¹H NMR (DMSO) δ13.65 (1H, brs), 8.76 (1H, s), 8.61 (1H, s), 8.11 (1H,s), 7.98 (1H, s), 3.99 (3H, s).

6,N-Methyl-4-methylthioimidazo[4,5-g]quinazoline. A solution of6,N-methyl-3H-imidazo[4,5-g]quinazolin-4-thione (1.08 g, 5 mmol) and KOH(0.40 g, 7 mmol) in 50% aqueous MeOH (100 mL) is treated with MeI (0.33mL, 5.3 mmol) and the resulting mixture is stirred at room temperaturefor 1 h. The methanol is then removed under reduced pressure, and theresidual aqueous solution is kept at 5° C. overnight to give crystals of6,N-methyl-4-methylthioimidazo[4,5-g]quinazoline (0.62 g, 54%). NMR(DMSO) δ8.93 (1H, s), 8.67 (1H, s), 8.22 (1H, s), 8.21 (1H, s), 4.01(3H, s), 2.74 (3H, s).

4-(3-Bromoanilino)-6,N-methylimidazo[4,5-g]quinazoline hydrochloride. Amixture of 6,N-methyl-4-methylthioimidazo[4,5-g]quinazoline (0.3 g, 1.3mmol), 3-bromoaniline-(0.34 g, 1.95 mmol), and 3-bromoanilinehydrochloride (0.41 g, 1.95 mmol) in isopropanol (400 mL) is heatedunder reflux for 6 h. After cooling the precipitated solid is collectedby filtration and recrystallized from EtOH to give4-(3-bromoanilino)-6,N-methylimidazo[4,5-g]quinazoline hydrochloride(0.43 g, 85%). ¹H NMR (DMSO) δ11.66 1H, brs), 9.43 (1H, s), 8.96 (1H,s), 8.80 (1H, s), 8.19 (1H, s), 8.16 (1H, brs), 7.89 (1H, brd, J=7.1Hz), 7.54-7.43 (2H, m), 4.05 (3H, s).

EXAMPLE 10 4-(3-Bromoanilino)pyrazino[2,3-g]quinazoline

7-Acetamido-6-nitro-3H-auinazolin-4-one. A solution of7-amino-6-nitro-3H-quinazolin-4-one (5.90 g, 28.6 mmol) [Leonard, N. J.;Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363] in amixture of glacial acetic acid (300 mL) and acetic anhydride (100 mL) isheated under reflux for 6 h, and water (100 mL) is added. The solutionis then concentrated to a small volume to give7-acetamido-6-nitro-3H-quinazolin-4-one (5.37 g, 76%). ¹H NMR (DMSO)δ10.51 (1H, brs), 8.57 (1H, s), 8.24 (1H, s), 7.97 (1H, s), 2.15 (3H,s).

7-Acetamido-4-(3-bromoanilino)-6-nitroquinazoline. A solution of7-acetamido-6-nitro-3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl₃ (250mL) is heated under reflux for 2 h, the excess of POCl₃ is removed undervacuum, and the residue is dissolved in CH₂Cl₂ and washed with aqueousNa₂CO₃ solution. Workup gives the crude 4-chloro derivative, which iscoupled directly with 3-bromoaniline in isopropanol as above, and theresulting hydrochloride is converted directly to the free base, bytreatment with aqueous NH₃, to give7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (3.60 g, 45%). ¹H NMR(DMSO) δ10.56 (1H, s), 10.29 (1H, s), 9.34 (1H, s), 8.70 (1H, s), 8.19(1H, brs), 7.97 (1H, s), 7.88 (1H, d, J=6.0 Hz), 7.43-7.35 (2H, m), 2.13(3H, s).

7-Amino-4-(3-bromoanilino)-6-nitroouinazoline. A solution of7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (1.50 g, 3.73 mmol)and KOH (2 g) in MeOH (190 mL) and H₂O (10 mL) is heated under refluxfor 30 min, and the solvent volume is reduced to give7-amino-4-(3-bromoanilino)-6-nitroquinazoline (1.17 g, 87%). ¹H NMR(DMSO) δ10.17 (1H, brs), 9.43 (1H, s), 8.43 (1H, s), 8.15 (1H,m brs),7.86 (1H, d, J=7.1 Hz), 7.42 (2H, brs), 7.40-7.31 (2H, m) , 7.12 (1H,s).

4-(3-Bromoanilino)-6,7-diaminoquinazoline. Iron dust reduction of7-amino-4-(3-bromoanilino)-6-nitroquinazoline (0.5 g, 1.4 mmol) in 65%aqueous EtOH containing sufficient aqueous HCl to ensure solubilitygives 4-(3-bromoanilino)-6,7-diaminoquinazoline (0.30 g, 65%). ¹H NMR(DMSO) δ9.14 (1H, s), 8.27 (1H, s), 8.23 (1H, brs), 7.85 (1H, d, J=8.0Hz), 7.31-7.14 (2H, m), 7.29 (1H, s), 6.79 (1H, s), 5.73 (2H, brs), 5.13(2H, brs).

4-(3-Bromoanilino)pyrazino[2,3-g]quinazoline. A mixture of4-(3-bromoanilino)-6,7-diaminoquinazoline (90 mg, 0.27 mmol) and1,4-dioxane-2,3-diol (0.2 g, 1.6 mmol) [Venuti, M. C.; Synthesis, 1982,61-63] in MeOH (20 mL) is stirred at room temperature overnight to givea precipitate of 4-(3-bromoanilino)pyrazino[2,3-g]quinazoline (80 mg,83%).

¹H NMR (DMSO) δ10.45 (1H, brs), 9.52 (1H, s), 9.09 (1H, d, J=1.6 Hz),9.06 (1H, d, J=1.6 Hz), 8.71 (1H, s), 8.44 (1H, s), 8.32 (1H, brs), 7.99(1H, m), 7.45-7.34 (2H, m).

EXAMPLE 11 4-(3-Bromoanilino)imidazolo[4,5-h]quinazoline hydrochloride

6-Methylthioimidazo[4,5-h]quinazoline. A solution of3H-imidazo[4,5--h]quinazoline-4-thione (0.41 g, 2 mmol) [Morrice, A. G.;Sprecker, M. A.; Leonard, N. J.; J. Org. Chem., 1975, 40, 363-366] andKOH (0.15 g, 27 mmol) in 50% MeOH-H₂O (50 mL) is treated with MeI (0.13mL) and the mixture is stirred at room temperature for 3 h to give aprecipitate of 4-methylthioimidazo[4,5-h]quinazoline (0.35 g, 80%).

¹H NMR (DMSO) δ13.80 (1H, brs), 9.09 (1H, s), 8.49 (1H, s), 7.98 (1H, d,J=8.8 HzH), 7.85 (1H, d, J=8.8 Hz), 2.72 (3H, s).

4-(3-Bromoanilino)imidazolo[4,5-h]quinazoline. A mixture of4-methylthioimidazo[4,5-h]quinazoline (0.216 g, 1 mmol), 3-bromoaniline(0.25 g, 1.5 mmol), and 3-bromoaniline hydrochloride (0.31 g, 1.5 mmol)in N-methylpyrrolidone (50 mL) is heated 120° C. for 2 h. The solvent isremoved under vacuum and the residue is triturated with EtOH to give asolid which is recrystallized from MeOH to give4-(3-bromoanilino)imidazo[4,5-h]quinazoline hydrochloride (0.23 g, 61%).¹H NMR (DMSO) δ11.11 (1H, brs), 8.93 (2H, s), 8.66 (1H, d, J=9.0 Hz),8.11 (1H, brs), 8.07 (1H, d, J=9.0 Hz), 7.83 (1H, brd, J=6.8 Hz),7.50-7.40 (2H,m).

EXAMPLE 12 4-(3-Bromoanilino)imidazolo[4,5-f]quinazoline

4-Methylthioimidazo[4,5-f]quinazoline. A solution of3H-imidazo[4,5-f]quinazoline-4-thione (1.01 g, 5 mmol) [Morrice, A. G.;Sprecker, M. A.; Leonard, N. J.; J. Org. Chem., 1975, 40, 363-366] andKOH (0.36 g, 6.5 mmol) in 50% MeOH-H₂O (50 mL) is treated with MeI (0.34mL) and the mixture is stirred overnight at room temperature. The MeOHis removed under vacuum to give a precipitate of4-methylthioimidazo[4,5-f]quinazoline (0.61 g, 57%). ¹H NMR (DMSO)δ13.23 (1H, m), 9.05 (1H, s), 8.60 (1H, s), 8.24 (1H, d, J=8.7 Hz), 7.81(1H, d, J=8.9 Hz), 2.71 (3H, S).

4-(3-bromoanilino)imidazo[4,5-f]quinazoline. A solution of4-methylthioimidazo[4,5-f]quinazoline (0.43 g, 2 mmol), 3-bromoaniline(0.5 g, 3 mmol), and 3-bromoaniline hydrochloride (0.63 g, 3 mmol) isheated under reflux for 16 h. The precipitate of hydrochloride salt isconverted directly to the free base with aqueous NH₃, and recrystallizedfrom EtOH to give 4-(3-bromoanilino)imidazo[4,5-f]quinazoline (0.52 g,77%). ¹H NMR (DMSO) δ11.53 (1H, brs), 8.79 (1H, s), 8.68 (1H, s), 8.53(1H, dd, J=1.8, 1.9 Hz), 8.15 (1H, d, J=8.8 Hz), 7.81 (1H, brd, J=8.6Hz), 7.71 (1H, d, J=8.9 Hz, 1 H), 7.41 (1H, t, J=8.0 Hz), 7.32 (1H, brd,J=7.8 Hz).

EXAMPLE 13 4-Benzylaminobenzothieno[3,2-d]pyrimidine

4-Chlorobenzothieno[3,2-d]pyrimidine (111 mg, 0.5 mmol), (see followingexperimental) and benzylamine (114 mg, 1.0 mmol) (111 mg, 1.1 mmol) instirred 2-propanol (2 mL) are heated at reflux under N₂ for 26 h. Themixture is allowed to cool, and the precipitate is collected by Buchnerfiltration, rinsed with 2-propanol and water and dried in an oven togive 4-benzylaminobenzothieno[3,2-d]pyrimidine (100 mg, 68%) as a whitepowder. ¹H NMR (DMSO) δ8.60 (1H, s), 8.51 (1H, t, J=5.9 Hz), 8.31 (1H,ddd, J=0.7, 1.4, 8.0 Hz), 8.17 (1H, ddd, J=0.7, 1.8, 8.1 Hz), 7.68 (1H,ddd, J=1.2, 7.0, 8.1 Hz), 7.59 (1H, ddd, J=1., 7.0, 8.1 Hz), 7.36 (2H,d, J=7.4 Hz), 7.33 (2H, t, J=7.3 Hz), 7.24 (1H, t, J 7.2 Hz), 4.79 (2H,d, J=6.0 Hz).

EXAMPLE 14 4-([R]-1-Phenylethylamino)benzothieno[3,2-d]pyrimidine

Ethyl 3-aminobenzothiophene-2-carboxylate. 2-Fluorobenzonitrile (0.61 g,5 mmol), ethyl thioglycollate (0.60 g, 5 mmol) and NEt₃ (1.52 g, 15mmol) are stirred in DMSO (5 mL) at 100° C. under N₂ for 3 h. Thereaction mixture is poured onto ice-water (50 mL), and the solid iscollected by suction filtration, rinsed with water, and air dried togive ethyl 3-aminobenzothiophene-2-carboxylate (0.78 g, 70%) as agrey-brown solid. ¹H NMR (DMSO) δ8.14 (1H, d, J=7.7 Hz), 7.88 (1H, d,J=8.1 Hz), 7.50 (1H, dt, J_(d)=1.2 Hz, J_(t)=7.5 Hz), 7.39 (1H, dt,J_(d)=1.2 Hz, J_(t)=7.6 Hz), 7.17 (2H, brs), 4.26 (2H, q, J=7.1 Hz),1.29 (3H, t, J=7.1 Hz).

Benzothieno[3,2-d]-3H-pyrimid-4-one: Ethyl3-aminobenzothiophene-2-carboxylate (764 mg, 3.45 mmol) is heated informamide (2 mL) under N₂ at 140° C. for 2 h, and at 180° C. for 20 h.The solution is allowed to cool to 25° C., and the slurry is diluted,with EtOH (5 mL). The solid is collected by suction filtration, rinsedwith EtOH (2×5 mL), and air dried to givebenzothieno[3,2-d]-3H-pyrimid-4-one (0.55 g, 79%) as a highlycrystalline dark brown solid. ¹H NMR (DMSO) δ12.85 (1H, brs), 8.35(1H,s), 8.16 (1H, d J=7.3 Hz), 7.67 (1H, dt, J_(d)=1.6 Hz, J_(t)=7.5Hz), 7.59 (1H, dt, J_(d)=1.2 Hz, J_(t)=7.5 Hz,).

4-Chlorobenzothieno[3,2-d]pyrimidine. DMF (0.27 g, 3.5 mmol) is addeddropwise to a solution of oxalyl chloride (0.44 g, 3.5 mmol) in1,2-dichloroethane (10 mL), stirred under N₂ at 25° C. When the vigorousgas evolution ceases, benzothieno[3,2-d]-3H-pyrimid-4-one (337 mg, 1.53mmol) is added and the reaction mixture is heated to reflux. After 20min, the reaction mixture is allowed to cool, and is then quenched withsaturated aqueous NaHCO₃ solution (20 mL). The phases are separated, andthe aqueous phase is extracted with CHCl₃ (3×10 mL). The combinedorganic phases are washed with water (2×10 mL), saturated brine (10 mL),and dried (Na₂SO₄). The solvent is removed under reduced pressure togive 4-chlorobenzothieno[3,2-d]pyrimidine (249 mg, 74%) as a light brownsolid. ¹H NMR (CDCl₃) δ9.09 (1H, s), 8.53 (1H, dd, J=1.8, 7.6 Hz), 7.95(1H, d, J=7.8 Hz), 7.73 (1H, dt, J_(d)=1.4 Hz, J_(t)=7.7 Hz), 7.62 (1H,dt, J_(d)=1.2 Hz, J_(t)=7.5 Hz).

4-([R]-1-Phenylethylamino)benzothieno[3,2-d]pyrimidine4-Chlorobenzothieno[3,2-d]pyrimidine (110.1 mg, 0.5 mmol),[R]-1-phenylethylamine (74 mg, 0.6 mmol) and NEt₃ (111 mg, 1.1 mmol) instirred propanol (2 mL) are heated at reflux under N₂ for 9 h. Themixture is allowed to cool, and is then purified by preparative tlc onsilica, eluting once with 2% MeOH in CHCl₃. The yellow solid isrecrystallized from EtOH at 0° C. to give4-([R]-1-phenylethylamino)benzothieno[3,2-d]pyrimidine, (75 mg, 49%) aspale yellow cubic crystals. ¹H NMR (DMSO) δ8.53(1H, s), 8.30(1H, d,J=7.2 Hz), 8.15 (1H, d, J=8.2 Hz), 7.68 (1H, dt, J_(d)=1.2 Hz, J_(t)=7.5Hz), 7.58 (1H, dt, J_(d)=1 Hz, J_(t)=7.5 Hz), 7.44 (1H, dd, J=1, 8 Hz),7.31 (2H, t, J=7.7 Hz), 7.21 (1 H, tt, J=1, 7.7 Hz), 5.58(1H, q, J=7Hz), 1.58 (3H, d, J=7 Hz).

EXAMPLE 15 4-(3-Bromoanilino)benzothieno[3,2-d]pyrimidine

4-Chlorobenzothieno[3,2-d]pyrimidine (110.1 mg, 0.5 mmol), (seepreceding example) 3-bromoaniline (107.2 mg, 0.62 mmol) and NEt₃ (102.8mg, 1.0 mmol) in stirred ethoxyethanol (2 mL) are heated at 110° C.under N₂ for 18 h. The solvent is removed under reduced pressure, andthe dark oily residue is purified by preparative layer chromatography,eluting once with 2% MeOH in CHCL₃. The major band R_(f) 0.40 isextracted to give a yellowish solid (147 mg) which is recrystallizedfrom EtOH (20 mL) to give 4-(3-bromoanilino)benzothieno[3,2-d]pyrimidine(70 mg, 39%) as pale beige glistening plates. ¹H NMR (CDCl₃) δ8.88(1H,s), 8.49(1H, dd, J=1.7, 7.1 Hz), 7.96 (1H, t, J=1.9 Hz), 7.89 (1H, dd,J=1.6, 7.0 Hz), (1H, d, J=7.8 Hz), 7.65 (1H, dt, J_(d)=1.55 Hz, J_(t)=7Hz), 7.60 (1H, dd, J=1.5, 7.5 Hz), 7.57 (1H, dt, J_(d)=1.5 Hz, J_(t)=7Hz), 7.40 (1H, dt, J_(d)=1.7 Hz, J_(t)=8 Hz), 7.28 (1H, t, J=7.8 Hz),6.90 (1H, brs).

EXAMPLE 16 4-(3-Bromoanilino)-8-nitrobenzo[b]thieno[3,2-d]pyrimidine

2-Fluoro-5-nitrobenzonitrile. A mixture of 70% nitric acid andconcentrated sulfuric acid (1:1, 30 mL) is added dropwise over 30 min toa solution of 2-fluorobenzonitrile (12.11 g, 0.10 mol) in concentratedsulfuric acid (50 mL), stirred under N₂ at 0° C. After a further 3 h at0° C. the yellow solution is poured onto ice (400 g), and the solid iscollected by Buchner filtration, rinsed with water (4×50 mL), and driedin vacuo to give 2-fluoro-5-nitrobenzonitrile (15.43 g, 93%) as a paleyellow crystalline solid. ¹H NMR (CDCl₃) δ8.56 (1H, dd, J=2.8, 5.5 Hz),8.51 (1H, ddd, J=2.8, 4.4, 9.1 Hz), 7.44 (1H, dd, J=7.8, 9.0 Hz).

Ethyl 3-amino-5-nitrobenzothiophene-2-carboxylate.2-Fluoro-5-nitrobenzonitrile (1.664 g, 10 mmol), ethyl thioglycollate(1.21 g, 10 mmol) and NEt₃ (3.06 g, 30 mmol) are stirred in DMSO (5 mL)at 100° C. under N₂ for h h. The deep orange-red reaction mixture ispoured onto ice-water (50 mL), and the solid is collected by suctionfiltration, rinsed with water, and dried in a vacuum oven at 60° C. togive ethyl 3-amino-S-nitrobenzothiophene-2-carboxylate (2.675 g, 100%)as a bright orange solid. ¹H NMR (DMSO) δ9.23 (1H, d, J=2.1 Hz), 8.28(1H, dd, J=2.3, 8.9 Hz), 8.10 (1H, d, J=9.0 Hz), 7.45 (2H, brs), 4.29(2H, q, J=7.1 Hz), 1.30 (3H, t, J=7.1 Hz).

8-Nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one. Ethyl3-amino-5-benzothiophene-2-carboxylate (2.66 g, 10 mmol) is heated informamide (10 mL) under N₂ at 190° C. for 4 h, and precipitates after 2h. The solution is allowed to cool to 25° C., and the solid is collectedby suction filtration, rinsed with EtOH (2×5 mL), and dried in a vacuumoven at 60° C. to give 8-nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one(1.91 g, 77%) as a highly crystalline orange-brown solid. ¹H NMR (DMSO)δ13.00 (1H, brs), 8.85 (1H,s), 8.45 (3H, s).

4-Chloro-8-nitrobenzo[b]thieno[3,2-d]pyrimidine. DMF (0.75 g, 10.3 mmol)is added dropwise to a solution of oxalyl chloride (1.27 g, 10 mmol) in1,2-dichloroethane (25 mL), stirred under N₂ at 25° C. When the vigorousgas evolution ceases, 8-nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one(1.236 g, 5 mmol) is added and the reaction mixture is heated to reflux.After 40 min, the hot reaction mixture is celite filtered, and thenrecrystallized at 0° C. to give4-chloro-8-nitrobenzothieno[3,2-d]pyrimidine (759 mg, 57%) as a lightbrown solid. ¹H NMR (DMSO) δ9.24 (1H, s), 8.99 (1H, d, J=2.0 Hz), 8.57,8.53 (1H, 1H, ABq of d, J_(AB)=9.0 Hz, J_(d)=2, 0 Hz).

4-(3-Bromoanilino)-8-nitrobenzo[b]thieno-[3,2-d]pyrimidine.4-Chloro-8-nitrobenzo[b]thieno-[3,2-d]pyrimidine (266 mg, 1.0 mmol),3-bromoaniline (187.4 mg, 1.1 mmol) and NEt₃ (200 mg, 2.0 mmol) instirred 1-propanol (4 mL) are heated at 110° C. under N₂ for 48 h,becoming a thick yellow paste. The mixture is cooled to 0° C., and thesolid is collected by Buchner filtration, and air dried to give4-(3-bromoanilino)-8-nitrobenzo[b]thieno[3,2-d]pyrimidine (275 mg, 69%)as a bright yellow solid. ¹H NMR (DMSO) δ10.12 (1H, brs), 9.03 (1H, s),8.88(1H, d, J=1.8 Hz), 8.54, 8.52 (1H, 1H, ABq of d, J_(AB)=7.5 Hz,J_(d)=0, 1.8 Hz), 8.18 (1H, d, J=1.7 Hz), 7.83 (1H, dd, J=1.5, 7.7 Hz),7.37, 7.34 (1H, 1H, ABq of d, J_(AB)=7.7 Hz, J_(d)=7.7, 1.5 Hz).

EXAMPLE 17 8-Amino-4-(3-bromoanilino)benzo[b]thieno[3,2-d]pyrimidine

4-(3-Bromoanilino)-8-nitrobenzo[b]thieno-[3,2-d]pyrimidine (97 mg, 0.24mmol) (see previous experimental) in THF (75 mL) is hydrogenated at 52psi for 3 h, in the presence of Raney nickel (5 mg). The reactionmixture is filtered, and the filtrate is concentrated to small volumeunder reduced pressure, and the residue is purified by preparative thinlayer chromatography on silica, eluting with 5% MeOH in CHCl₃. The bandRf 0.28 is extracted to give8-amino-4-(3-bromoanilino)benzo[b]thieno[3,2-d]pyrimidine (47.2 mg, 53%)as a yellow solid. ¹H NMR (DMSO) δ9.66 (1H, brs), 8.72 (1H, s), 8.18(1H, t, J=1.9 Hz), 7.84 (1H, ddd, J=1.2, 2.0, 8.1 Hz), 7.78 (1H, d,J=8.5 Hz), 7.50 (1H, d, J=2.2 Hz), 7.33 (1H, t, J=8.1 Hz), 7.27 (1H,ddd, J=1.2, 1.8, 8.0 Hz), 7.02 (1H, dd, J=2.3, 8.5 Hz), 5.47 (2H, brs).

EXAMPLE 18 4-(3-Bromoanilino)-9-methoxybenzo[b]thieno[3,2-d]pyrimidinehydrochloride.

2-Fluoro-6-methoxybenzaldoxime. NH₂OHHCl (334 mg, 4.76 mmol) is added inportions to a solution of NaHCO₃ (395 mg, 4.7 mmol) in water (10 mL) atr.t. To this solution was added dropwise a mixture of2-fluoro-6-methoxybenzaldehyde (made from 3-fluoroanisole as describedin Tetrahedron Lett. 1992, 33, 7499) (725 mg, 4.7 mmol) and EtOH (10mL). The resulting mixture is stirred at r.t for 2 hr. The precipitateis collected by filtration and dried in a vacuum oven at ˜50° C.overnight to give 2-fluoro-6-methoxybenzaldoxime (720 mg, 89%)). ¹H NMR(DMSO) δ11.44, (1H, s), 8.16 (1H, s), 7.40, (1H, m) 6.85-6.95 (2H,m),3.84 (3H, s).

2-Fluoro-6-methoxybenzonitrile. A solution of2-fluoro-6-methoxybenzaldoxime (714 mg, 4.2 mmol) in Ac₂O (3.6 mL) isheated at reflux for 4 hr. The reaction is cooled to r.t. and thevolatiles are stripped off to give a beige solid, which is dried at 50°C. in a vacuum oven to give 2-fluoro-6-methoxybenzonitrile (635 mg,84%). ¹H NMR (DMSO) δ7.8-7.7 (1H, m), 7.14-7.07 (2H, m),3.95 (3H, s).

Methyl 3-amino-4-methoxybenzothiophene-2-carboxylate. Methylthioglycollate (0.18 mL, 1.9 mmol) is added dropwise to a suspension ofNaH (60% oil suspension, 176 mg, 4.4 mmol) in DMSO (5 mL), stirred underN₂ at 25° C. When gas evolution ceases, 2-fluoro-6-methoxybenzonitrile(266 mg, 1.76 mmol) inDMSO 5 mL is added in one portion. After 3 h, thereaction mixture is poured onto ice-water, and the beige precipitate iscollected by suction filtration, rinsed and air dried to give methyl3-amino-4-methoxybenzothiophene-2-carboxylate (345 mg, 83%). ¹H NMR(DMSO) δ7.44-7.37 (2H, m), 7.00, (2H brs), 6.90 (1H, d, J=7.7 Hz), 3.95(3H, s), 3.76 (3H, s).

9-Methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine. A mixture of methyl3-amino-4-methoxybenzothiophene-2-carboxylate (202 mg, 0.85 mmol) andformamide (2 mL) is heated at 135 C. for 1 hr and the temperature israised to 190 C. After 8 hr the reaction is cooled to r.t. Upon-cooling,black solid forms and is collected by filtration. The precipitate is airdried to give 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (45 mg,22.5%). ¹H NMR (DMSO) δ12.0 (1H, brs), 8.31 (1H, s)7.70-7.55 (2H, m),7.10 (1H, d, J=7.7 Hz), 3.97 (3H, s).

4-Chloro-9-methoxybenzothieno[3,2-d]pyrimidine. DMF (0.125 mL, 1.7 mmol)is added dropwise to a solution of (COCl)₂ (0.15 mL, 1.68 mmol) in1,2-dichloroethane (4.5 mL) at r.t. After gas evolution ceases,9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (73.2 mg, 0.32 mmol) isadded. The resulting mixture is heated at reflux for 4 hr. After thereaction is cooled to r.t., the black tar is filtered off. The filtrateis stripped to dryness and then mixed with water. A yellow solid formsand is collected via filtration. The solid is washed with water and airdried to give 4-chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg,66%). ¹H NMR (DMSO) δ9.17 (1H, s), 7.82-7.78 (2H, m), 7.3-7.2 (1H, m) ,4.06 (3H, s).

4-(3-bromoanilino)-9-methoxybenzo[b]thieno-[3,2-d]pyrimidinehydrochloride. A mixture of4-chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg, 0.21 mmol),2-methoxyethanol (3 mL) and m-bromoaniline (0.03 mL, 0.28 mmol) isheated at 80 C. for 1 h. The reaction is cooled to r.t. and yellow solidprecipitates. The solid is collected by filtration and dried in a vacuumoven at ˜50 C. overnight to give4-(3-bromoanilino)-9-methoxybenzo[b]thieno[3,2-d]pyrimidinehydrochloride (60 mg, 68%). ¹H NMR (DMSO) δ11.14 (1H, brs), 8.95 (1H,s), 8.07 (1H, d, J=1.7 Hz), 7.87 (1H, d, J=8.2 Hz), 7.80 (1H, d, J=8.2Hz), 7.76 (1H, d, J=7.5 Hz), 2.49 (1H, d, J=8.2 Hz), 7.44 (1H, t, J=8.0Hz), 7.25 (1H, d, J=8.0 Hz), 4.10 (3H, s).

EXAMPLE 19 4-(3-Bromoanilino)thiazolo[4′,5′; 4,5]thieno[3,2-d]pyrimidine

A mixture of 5-chlorothiazolo[4′,5′;4,5]-thieno[3,2-d]pyrimidine(prepared as described by Athmani and Iddon, Tetrahedron , 48, 7689,1992) (66 img, 0.29 mmol), 3-bromoaniline (0.033 mL, 0.3 mmol) and2-methoxyethanol (3 mL) is heated at 95 C. for 2.5 h and then cooled toroom temperature. The reaction is added to water, and the precipitate iscollected by Buchner filtration and purified by preparative tic onsilica (2% MeOH/CHCl₃). The major band is extracted with 20% MeOH/CHCl₃.After removal of the solvent under reduced pressure4-(3-bromoanilino)thiazolo[4′,5′; 4,5]thieno[3,2-d]pyrimidine (25 mg,23%) is obtained.

¹H NMR (DMSO) δ9.98 (1H, s), 9.67 (1H, s), 8.75 (1H,s), 8.17 (1H, s),7.82 (1H, d, J=7.8 Hz), 7.38-7.31 (2H, m).

EXAMPLE 20 4-(3-Chloroanilino)pyrido[3′, 2′:4,5]thieno[3,2-d]pyrimidine

Ethyl 3-aminopyrido[3,2-b]thiophene-2-carboxylate. A solution of2-chloro-3-cyanopyridine (0.14 g, 1.0 mmol) in DMSO (2 mL) is addeddropwise to a mixture of ethyl thioglycolate (0.12 mL, 1.1 mmol), NaH(0.06 g, 1.5 mmol) and DMSO (1 mL) stirred under N₂ at 25° C. After 3 hthe reaction is worked up by pouring the reaction mixture onto stirredice water. The light yellow precipitate is collected by Buchnerfiltration and dried in a vacuum oven to give ethyl3-aminopyrido[3,2-b]thiophene-2-carboxylate (197 mg, 89%). ¹H NMR (DMSO)δ8.68 (1H, dd, J=4.6, 1.6 Hz), 8.54 (1H, dd. J=8.2, 1.6 Hz), 7.46 (1H,dd, J=8.2, 4.5 Hz), 7.31 (2H, brs), 4.3 (2H, q, J=7.1 Hz), 1.29 (3H, t,J=7.1 Hz).

3H-Pyrido[3′,2′, 4,5]thieno[3,2-d]pyrimid-4-one. A mixture of ethyl3-aminopyrido[3,2-b]thiophene-2-carboxylate (0.92 g, 4.14 mmol) andformamide (10 mL) is heated at 135 C. for 1 h and then at 190 C. for 4h. The reaction mixture is cooled to 25° C. producing a precipitate. Thesolid is collected by vacuum filtration and is washed with water anddried in a vacuum oven at 60° C. to give 3H-pyrido[3′, 2′;4,5]thieno[3,2-d]pyrimid-4-one (0.61 g, 72.6%) as yellow-brown needles.¹H NMR (DMSO) δ13.0 (1H, brs), 8.86 (1H, dd, J=4.6, 1.6 Hz), 8.63 (1H,dd, J=8.0, 1.6 Hz), 8.4 (1H, s), 7.68 (1H, dd, J=8.1, 4.6 Hz).

4-Chloropyrido[3′,2′; 4,5]thieno[3,2-d]pyrimidine. To a solution of(COCl)₂ (1.3 mL,15 mmol) in 1,2-dichloroethane (75 mL) DMF (1.1 mL, 15mmol) is added dropwise and stirred under N₂ at 25° C. After gasevolution ceases, 3H-pyrido[3′,2′; 4,5]thieno[3,2d]pyrimid-4-one (0.61g, 3.0 mnmol) is added to the mixture and the temperature is raised to85 C. After 2 h, the reaction mixture is cooled to 25° C. and extractedwith CHCl₃. The combined extracts are washed with water, saturated brineand dried (MgSO₄). The solvent is removed in vacuo to give4-chloropyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine (0.64 g, 96%) as ayellow solid. ¹H NMR (DMSO) δ9.3 (1H, brs), 9.0 (1H, d, J=1.7 Hz), 8.9(1H, dd, J=7.3, 0.8 Hz), 7.8 (1H, dd, J=4.7, 0.8 Hz).

4-(3-Chloroanilino)pyrido[3′, 2′:4.5]thieno[3,2-d]pyrimidine. A mixtureof 4-chloropyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine (0.12 g, 0.54mmol), 3-chloroaniline (0.06 mL, 0.5 mmol) and 2-ethoxyethanol (5 mL) isheated under N₂ with stirring at 135 C. for 3 h. Upon cooling a solidprecipitates. The solid is collected by filtration, washed with acetoneand dried in a vacuum oven at −80 C. to give4-(3-chloroaniline)pyrido[3′, 2′;4,5]thieno[3,2-d]pyrimidine (46 mg,27%). ¹H NMR (DMSO) δ9.97 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz), 8.85(1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.08 (2H, t, J=2.0 Hz), 7.79 (1H,ddd, J=8.3, 2.0, 0.0 Hz), 7.69 (1H, dd, J=8.0, 4.6 Hz), 7.43 (1H, t,J=8.0 Hz), 7.19 (1H, ddd, J=8.0, 2.0, 0.8 Hz).

EXAMPLE 21 4-(3-bromoanilino)pyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine

A mixture of 4-chloropyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine (72 mg,0.32 mmol) (see previous experimental), 3-bromoaniline (0.04 mL, 0.37mmol) and 2-ethoxyethanol (5 mL) is heated under N₂ with stirring at 135C. for 3 h. Upon cooling a solid precipitates. The solid is collected byfiltration, washed with acetone and dried in a vacuum oven at ˜80 C. togive 4-(3-bromoanilino)pyrido[3′, 2′; 4,5]thieno[3,2-d]pyrimidine (45mg, 39.4%). ¹H NMR (DMSO) δ9.96 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz),8.85 (1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.20 (1H, t, J=2.0 Hz), 7.84(1H, ddd, J=8.0, 2.0, 1.3 Hz), 7.69 (1H, dd, J=8.0, 4.7 Hz), 7.39-7.31(2H, m).

EXAMPLE 22 4-Anilinoindolo[3,2-d]pyrimidine

A solution of 4-chloroindolo[3,2-d]pyrimidinehydrochloride (240 mg, 1.0mmol) [Monge, A.; Palop, J. A.; Goni, T.; Martinez-Crespo, F.; Recalde,I. J. Het. Chem., 1986, 23, 647-9.], and aniline (0.273 mL, 3 mmol) inethanol (1 mL) is heated at reflux for 3 h, during which time thereaction becomes a thick suspension. After cooling to 25 C. and dilutingwith ethanol (4 ml) the mixture is filtered, and the crude productwashed with water (15 mL), and ethanol (15 mL), giving 274 mg tan solid,which is recrystallized from DMF/water affording pure4-anilinoindolo[3,2-d]pyrimidine hydrochloride (82 mg, 27%). ¹H NMR(DMSO): δ12.79 (1H, brs), 11.04 (1H, brs), 8:94 (1H, s), 8.27 (1H, d,J=8.2 Hz), 7.96 (2H, d, J=7.5 Hz), 7.85 (1H, d, J=8.4 Hz), 7.71 (1H, t,J=7.7 Hz), 7.49 (2H, t, J=8.0 Hz), 7.41 (1H, t, J=7.6 Hz), 7.24 (1H, t,J=7.4 Hz).

EXAMPLE 23 4-Benzylaminoindolo[3,2-d]pyrimidine

4-Chloroindolo[3,2-d]pyrimidine hydrochloride (240 mg, 1 mmol, andbenzylamine (1 mL) are stirred under a dry nitrogen atmosphere at 150 C.for 6 hours, and then concentrated under reduced pressure to give anoily soft solid which is dissolved in EtOAc (20 mL), and washed withsaturated sodium bicarbonate solution (20 mL), water (3×15 mL), andbrine (20 mL). The solution is dried (MgSO₄) and the solvent is removedunder reduced pressure. Trituration of the residue with dichloromethane,gives 4-benzylaminoindolo[3,2-d]pyrimidine (190 mg, 69%).

¹H NMR (CDCl₃): δ10.58 (1H, brs), 8.60 (1H, s), 8.08 (1H, d, J=8.0 Hz),7.47-7.14 (8H, m), 4.82 (2H, d, J=5.6 Hz), 2.41 (1H, brs).

EXAMPLE 24 4-([R]-1-Phenylethylamino)indolo[3,2-d]pyrimidinehydrochloride

4-Chloroindolo[3,2-d]pyrimidine hydrochloride 240 mg, 1 mmol) and(R)-(+)-methylbenzylamine (1 ml) are stirred under a dry nitrogenatmosphere at 150 for 5 hours, and then concentrated under reducedpressure to an oil. This oil is dissolved in EtOAc (20 ml), and stirredfor 16 h. The precipitate which forms is collected by filtration, washedwith EtOAc, and dried at 90 in vacuo to give4-([R]-1-phenylethylamino)indolo[3,2-d]pyrimidine hydrochloride (37 mg,11%). ¹H NMR (DMSO): δ10 (1H, s), 9.14 (1H, brs), 8.64 (1H, s), 8.16(1H, d, J=8.0 Hz), 7.74 (1H, d, J=8.5 Hz), 7.63-7.59 (1H, m), 7.50 (2H,d, J=7.2 Hz), 7.38-7.24 (4H, m), 5.59 (1H, p, J=7.0 Hz); 1.64 (3H, d,J=7.0 Hz).

EXAMPLE 25 4-(3-Bromoanilino)indolo[3,2-d]pyrimidine hydrochloride

4-Choroindolo[3,2-d]pyrimidine hydrochloride (240 mg, 1 mmol) and3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated at refluxunder a nitrogen atmosphere for 2 h. Filtration and washing of thecollected solids with ethanol, followed by recrystallization from DMFgives 4-(3-bromoanilino)indolo[3,2-d]pyrimidine hydrochloride (288 mg,77%). ¹H NMR (DMSO) δ12.73 (1H, s), 11.42 (1H, s), 9.02 (1H, s), 8.41(1H, s), 8.28 (1H, d, J=7.9 Hz), 7.95-7.92 (1H, m), 7.84-7.82 (1H, d,J=8.6 Hz), 7.74-7.69 (1H, m), 7.40-7.47 (3H, m).

EXAMPLE 26 4-(3-Bromoanilino)-5,N-methylindolo[3,2-d]pyrimidinehydrochloride

A solution of 4-chloro-5,N-methylindolo[3,2-d]pyrimidine (Kadushkin, A.V.; Nesterova, I. N.; Golovko, T. V.; Nikolaeva, I. S.; Pushkina, T. V.;Fomina, A. N.; Sokolova, A. S.; Chernov, V. A.; Granik, V. G.Khim.-Farm. Zh. 1990 , 24, 18-22) (218 mg, 1 mmol) and 3-bromoaniline(0.33 mL, 3 mmol) in 2-propanol (7 mL) containing 0.5% HCl gas is heatedat reflux for 3 hr, cooled to 25 C., and the solids are filtered andwashed with 2-propanol and dried affording4-(3-bromoanilino)-5,N-methylindolo[3,2-d]pyrimidine hydrochloride (379mg, 97%), as a bright yellow solid. ¹H NMR (DMSO) δ9.80 (1H, s), 8.83(1H, s), 8.34 (1H, d, J=8.0 Hz.), 7.95-7.90 (2H, m), 7.79-7.68 (3H, m),7.45-7.41 (3H, m), 4.27 (3H, s).

EXAMPLE 27 4-Anilinoindolo[2,3-d]pyrimidine

4-Chloroindolo[2,3-d]pyrimidine hydrochloride (R. G. Glushkov et. al.,Khim.-Farm. Zh., 1967, 1(9), 25-32) (240 mg, 1 mmol) and aniline (0.27mL, 3 mmol) in ethanol (1 mL) are heated under reflux for 6 h. Thesolvent is evaporated under reduced pressure, and the residue trituratedwith EtOAc to afford a tan powder which is filtered, and washed withcold ethanol. Recrystallization from acetone/pet. ether gives4-anilinoindolo[2,3-d]pyrimidine (49 mg, 19%). ¹H NMR (DMSO) δ1H, s),8.84 (1H, s), 8.43 (1H, s), 8.37 (1H, d, J=8.0 Hz), 7.74 (2H, d, J=7.7Hz), 7.52-7.08 (6H, m).

EXAMPLE 28 4-(3-Bromoanilino)indolo[2,3-d]pyrimidine hydrochloride

4-Chloroindolo[2,3-d]pyrimidine hydrochloride (240 mg, 1 mmol) and3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated underreflux for 2 h. The solids are collected by suction filtration, washedwith ethanol and dried to give 4-(3-bromoanilino)indolo[2,3-d]pyrimidinehydrochloride (248 mg, 73%). ¹H NMR (DMSO) δ1H, s) , 9.02 (1H, s),8.51(1H, s), 8.42 (1H, d, J=7.7 Hz), 8.08 (1H, t, J=1.9 Hz), 7.82 (1H, d, J8.0 Hz), 7.53 (1H, d, J=7.9 Hz), 7.46 (1H, dt, J_(d)=1.0 Hz, J_(t)=7.6Hz), 7.36-7.27 (3H, m).

EXAMPLE 29 4-(3-Bromoanilino)-9,N-methylindolo[2,3-d]pyrimidine.

4-Chloro-9,N-methylindolo[2,3-d]pyrimidine (Portnov, Yu. N.; Bulaga, S.N.; Zabrodnyaya, V. G.; Smirnov, L. D. Khim. Geterotsikl. Soedin., 1991, 3, 400-2) (220 mg, 1 mmol) and 2-bromoaniline (0.33 mL, 3 mmol) in2-propanol, containing 0.5% (w:w) HCl gas, (7 mL) is heated under refluxfor 6 h. After removal of solvent under reduced pressure, the residue issuspended in CHCl₃ (50 mL), and washed with 1% aqueous NaOH solution (25mL), and H₂O (2×20 mL), dried (MgSO₄), and concentrated under reducedpressure. Column chromatography (SiO₂) with CHCl₃ gives the product as alight tan foam, which slowly crystallizes upon standing at 25 C.Recrystallization from diisopropyl ether (˜30 ml) affords4-(3-bromoanilino)-9,N-methylindolo[2,3-d]pyrimidine (220 mg, 65%)as afluffy white solid. ¹H NMR (CDCl₃) δs,s,m, 3.96 (3H, s).

EXAMPLE 304-(3-Bromoanilino)-9N-(2-N,N-diethylaminoethyl)pyrimido[2,3-d]indole bishydrochloride

4-Chloro-9N-(2-(N,N-diethylamino)ethyl)-indolo[2,3-d]pyrimidine. Asuspension of 4-chloroindolo[2,3-d]pyrimidine hydrochloride (407 mg, 2mmol), 2-N,N-diethylaminoethyl chloride hydrochloride (413 mg, 2.4mmol), anhydrous cesium carbonate (1.95 g, 6 mmol) and 4 molecularsieves (1.5 g) in acetone (6 mL) are heated at reflux under a nitrogenatmosphere for 1.5 h. The mixture is filtered through celite, washingthe filter cake with acetone (4×10 ml), followed by concentration of thefiltrate under reduced pressure affording a viscous amber oil, which isdissolved in CH₂Cl₂, (20 ml), and washed with water (2×25 mL), dried(MgSO₄), and the solvent is removed in vacuo. The crude product ischromatographed on silica, eluting with 4% methanol/chloroform to give4-chloro-9N-(2-(N,N-diethylamino)ethyl)indolo[2,3-d]pyrimidine (495 mg,82%), as a pale yellow oil. ¹H NMR (DMSO) δ8.79 (1H, s), 8.41 (1H, d,J=8.0 Hz), 7.66-7.58 (2H, m), 7.46-7.42 (1H, m), 4.57 (2H, t, J=6.8 Hz),2.90 (2H, t, J=7.1 Hz), 2.63 (4H, d, J=7.0 Hz), 0.99 (6H, t, J=7.0 Hz).

4-(3-Bromoanilino)-9N-(2-N,N-diethylamino-ethyl)pyrimido[2,3-d]indolebis hydrochloride. A suspension of4-chloro-9N-(2-(N,N-diethylamino)ethyl)-indolo[2,3-d]pyrimidine (240 mg,1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in 2-propanol (7 mL), whichcontains 0.5% HCl gas, is heated under reflux for 6 hr, and thenconcentrated to a viscous brown oil which is dissolved in chloroform (75mL) and washed with 1% aqueous NaOH solution (50 mL), water (50 mL), anddried (MgSO₄). The solvent is removed under reduced pressure, and theresidue is chromatographed on Sio₂ eluting with 2% MeOH in CHCL₃ toobtain the free base of the product as a pale yellow oil (411 mg, 93%).The free base is dissolved in warm ethanol (5 mL), and is treated withethanol (2 mL) which had been saturated with HCl gas, affording4-(3-bromoanilino)-9N-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidinebis hydrochloride. 1H NMR (DMSO) δ10.64 (1H, brs), 9.17 (1H, s), 8.60(1H, s), 8.52 (1H, d, J=8.0 Hz), 8.07 (1H, s), 7.93 (1H, d), 7.80 (1H,d, J=7.7 Hz), 7.58 (1H, t, J=7.7 Hz), 7.41 (1H, t, J=7.2 Hz), 7.37-7.39(2H, m), 4.90 (2H, t, J=7.0 Hz), 3.51 (2H, dd, J=12.8, 6.5 Hz) 3.31-3.28(4H, m), 1.25 (6H, t, J=7.2 Hz).

EXAMPLE 31 4-(3-Bromoanilino)6-methoxyindolo[2,3-d]pyrimidine

Cyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester. To an ice-coldsolution of ethyl cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF(170 mL) under N₂ is added of potassium tert-butoxide (12.07 g, 107.5mmol). The formed white suspension is stirred for 15 min then treatedwith 3-fluoro-4-nitroanisole [Halfpenny, P. R.; Horwell, D. C.; Hughes,J.; Hunter, J. C.; Rees, D. C. J. Med. Chem. (1990), 33, 286-91] (8.86g, 51.2 mmol). The suspension is heated at reflux for 1.5 h. Thesolution is poured into H₂O; and the aqueous mixture is acidified to pH2 with concentrated HCl. The mixture is extracted three times with etherthen the combined organic phases are dried (MgSO₄) and concentrated toan oil that is pumped at 0.3 mm for 2 days. The oil is dissolved indichloromethane and purified by flash silica gel chromatography elutingwith dichloromethane. The product fractions are combined andconcentrated to leave cyano-(5-methoxy-2-nitrophenyl)acetic acid ethylester (14.5 g) as a light yellow oil that is about 93-95% pure. ¹H NMR(CDCl₃): δ8.29 (1H, d, J=9.2 Hz), 7.22 (1H, d, J=2.7 Hz), 7.04 (1H, dd,J=9.2, 2.7 Hz), 5.69 (1H, s), 4.31 (2H, q, J=7.0 Hz), 1.34 (3H, t, J=7.2Hz).

2-Amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester. A solution ofcyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester (13.2 g, 46.3mmol, 93-95% pure) in glacial acetic acid (185 mL) is treated with asingle charge of zinc dust (12.1 g, 185 mmol). The mixture is heated at55° C. for 45 min, then treated with more zinc (4 g). After heating foranother 105 min, the brown mixture is filtered through a pad of flashsilica gel. The pad is washed well with acetic acid and the filtrate isconcentrated to a residue that is distributed between dichloromethaneand H₂O. The organic phase is washed with 5% aqueous sodium bicarbonateand concentrated to a residue that shows about a 1:1 mixture of productsby silica gel thin layer chromatography (dichoromethane:EtOAc, 3:1). Theresidue is purified by flash silica gel chromatography elutingsequentially with 100:0, 95:5, and 90:10 dichloromethane:EtOAc. Thefractions containing the pure higher Rf product are combined andconcentrated to a solid that is sonicated in tert-butyl methyl ether.The solids are collected by filtration to give pure2-amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester (2.07 g) as anoff-white solid. Further chromatography of the combined mother liquorand impure fractions affords 120 mg of additional product. Totalyield=2.19 g (20%). ¹H NMR (DMSO): δ10.44 (1H, br s, exchanges withD₂O), 7.11 (1H, d, J=2.2 Hz), 6.98 (1H, d, J=8.4 Hz), 6.61 (2H, br s,exchanges with D₂O), 6.48 (1H, dd, J=8.4, 2.7 Hz), 4.20 (2H, q, J=7.0Hz), 3.71 (3H, s), 1.32 (3H, t, J=7.2 Hz).

6-Methoxy-3H-indolo[2,3-d]pyrimidine-4-one. A solution of2-amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester (2.15 g (9.2mmol), sodium methoxide (0.5 g (9.3 mmol), and formamide (200 mL), isheated under N₂ at 220° C. for 1.5 h. The solution is cooled to roomtemperature, stored for 2.5 days, and filtered. The solvent isevaporated by Kugelrohr distillation at 95° C./0.8 mm. The residualsolids are washed with H₂O, then heated in 35 mL of boilingN,N-dimethylformamide. The hot suspension is filtered hot over a pad offlash silica gel. The cooled filtrate is concentrated in vacuo to asolid that is sonicated in about 30 mL of MeOH. The solids are filtered,washed with MeOH, and dried to leave6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (1.71 g, 72%) that is about83% pure. ¹H NMR (DMSO) δ12.16 (1H, br s, exchanges with D₂O), 12.04(1H, br s, exchanges with D₂O), 8.08 (1H, d, J=3.4 Hz, exchanges to swith D₂O), 7.46 (1H, d, J=1.9 Hz), 7.37 (1H, d, J=8.7 Hz), 6.95 (1H, dd,J=8.8, 2.5 Hz), 3.81 (3 H, s).

4-Chloro-6-methoxyindolo[2,3-d]pyrimidine. A suspension of6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (800 mg, 3.08 mmol, ˜83%pure) and POCl₃ (7 mL) is heated at 90° C. for 6 h. The suspension isconcentrated to a solid that is evacuated at 1 mm for 1 h. The solidsare cooled in a −78° C. bath then treated dropwise with cold H₂O. Thebath is removed and the frozen solids are allowed to gradually melt. Thesolids are filtered, washed well with cold H₂O, and dried to leave4-chloro-6-methoxyindolo[2,3-d]pyrimidine dine (733 mg, 81%) that isabout 80% pure. ¹H NMR (DMSO): δ12.64 (1H, br s, exchanges with D₂O),8.74 (1H, s), 7.74 (1H, d, J=2.4 Hz), 7.57 (1H, d, J=8.9 Hz), 7.28 (1H,dd, J=8.9, 2.4 Hz), 3.88 (3H, s).

4-(3-Bromoanilino)-6-methoxyindolo[2,3-d]pyrimidine. A mixture of4-chloro-6-methoxyindolo-[2,3-d]pyrimidine (107 mg, 0.37 mmol, 80%pure), 3-bromoaniline (0.15 mL, 1.4 mmol), N,N-dimethylacetamide (1 mL),and 1 drop of a solution of 2-propanol that is 8.5 molar in HCl isheated under N₂ at 120° C. for 5 h. The solution is concentrated invacuo to an oily solid that is triturated in 5% aqueous sodiumbicarbonate. The solids are collected by filtration, then washedsuccessively with H₂O and EtOAc. The solids are warmed in a small volumeof N,N-dimethylformamide and filtered. The filtrate is purified by thicklayer silica gel chromatography eluting with 3:2 dichloromethane:EtOAc.The product band is collected and sonicated in EtOAc. The mixture isfiltered and the filtrate is concentrated to a solid that is sonicatedin MeOH. The solids are collected, washed with MeOH, and dried to givepure 4-(3-bromoanilino)-6-methoxyindolo[2,3-d]pyrimidine (39 mg, 28%)hydrated with 0.7 equivalent of H₂O. ¹H NMR (DMSO): δ11.99 (1H, br s,exchanges with D₂O), 8.97 (1H, br s, exchanges with D₂O), 8.44 (1H, s),8.02 (1H, s), 7.91 (1H, d, J=2.4 Hz), 7.76 (1H, d, J=8.0 Hz), 7.42 (1H,d, J=8.7 Hz), 7.36-7.24 (2H, m), 7.08 (1H,dd, J=8.7, 2.2 Hz), 3.87 (3H,s).

EXAMPLE 32 2-Amino-4-(3-bromoanilino)pyrimido[2,3-d]indole

2-Guanidinoindole-3-carboxylic acid ethyl ester hydrochloride. Asuspension of 2 aminoindole-3-carboxylic acid ethyl ester (2.04 g, 10.0mmol), cyanamide (534 mg, 12.7 mmol), and concentrated hydrochloric acid(1 mL) in dioxane (91 mL), are heated under reflux for 48 hr. After thereaction mixture has cooled to 25 C. it is filtered and the solidswashed well with dry diethyl ether, and then air dried to give2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.08 g,38%) 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride as anoff-white solid, mp >250 C.

2-Amino-4-oxo-3H-indolo[2,3-d]pyrimidine. A mixture of2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.00 g,3.5 mmol) and sodium hydroxide (1.5 g) in water (50 mL) is heated togentle reflux for 6 hr followed by the addition of sufficient 5% HCl toadjust the solution to pH 1, and filtration of the resulting mixturethrough celite, washing the pad with water. The filtrate is extractedwith ethyl acetate (3×25 mL), and then basified with solid sodiumcarbonate. The tan precipitate which slowly forms is collected byfiltration, washed with water, and dried in vacuo affording2-amino-4-oxo-3H-indolo[2,3-d]pyrimidine (561 mg, 78%) as light tancrystals, mp >275 C.

2-Amino-4-chloroindolo[2,3-d]pyrimidine hydrochloride. A suspension of2-amino-4-oxo-3H-indolo[2,3-d]pyrimidine (490 mg, 2.5 mmol) andphosphoryl chloride (7 ml, 75 mmol) in dioxane (13 ml) is heated underreflux for 4 hr, then concentrated in vacuo. The residue is trituratedwith ethanol, filtered, and the solids washed with 10:1 Ethanol:EthylAcetate to give 170 mg (27%) 2-amino-4-chloroindolo[2,3-d]pyrimidinehydrochloride as a grey solid, mp >250 C.

2-Amino-4-(3-bromoanilino)indolo[2,3-d]pyrimidine. A mixture of2-amino-4-chloroindolo[2,3-d]pyrimidine hydrochloride (123 mg, 0.6 mmol)and 3-bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is heated atreflux for 4 hr, filtered through a celite pad, and concentrated invacuo. The residue is partitioned between ethyl acetate (25 mL) andwater (25 mL). The aqueous phase is extracted with further ethyl acetate(2×20 mL), followed by washing the combined extracts with 1% aqueoussodium hydroxide (25 mL), water (2×40 mL) , saturated brine (40 mL), anddrying (Na₂SO₄). The solution is evaporated to dryness under reducedpressure to afford 105 mg crude product as a tan powder. The solid isdissolved in a minimum amount of methanol, filtered, and furtherpurified by preparative plate chromatography (SiO₂; 1:1, EtOAc:CH₂Cl₂;R_(f)=0.40). After extraction of the product from the silica gel withethyl acetate, the volume of the warm solution is reduced to minimum, and it is filtered through celite, and the solvent is removed underreduced pressure. The oily solid thus obtained is dissolved in a minimumamount of 2-propanol and allowed to crystallize at 3 C. over an 18 hperiod. The crystals are collected by suction filtration, washed with asmall amount of cold 2-propanol, and dried in vacuo to give2-amino-4-(3-bromoanilino)indolo[2,3-d]pyrimidine (34 mg, 17%). ¹HNMR,(DMSO): δbrs), 8.57 (1H, s), 8.11 (1H, d, J=8.0 Hz), 8.01 (1H, s), 7.94(1H, d, J=8.2 Hz), 7.34-7.12 (5H, m), 6.41 (2H, brs).

EXAMPLE 334-(3-Bromoanilino)-9N-(2-N,N-diethylaminoethyl)-6-methoxyindolo[2,3-d]pyrimidinebishydrochloride

4-Chloro-6-methoxy-9H-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidine.A suspension of 4-chloro-6-methoxyindolo[2,3-d]pyrimidine (773 mg, 2.5mmol, ˜80% pure), 2-diethylaminoethyl chloride hydrochloride (582 mg,3.4 mmol), anhydrous cesium carbonate (2.3 g, 7.1 mmol), 4 molecularsieves (2.1 g), and acetone:N,N-dimethylformamide (12 mL, 2:1) is heatedat reflux under N₂ for 16.5 h. The mixture is filtered over Celite® andthe filter pad is washed well with acetone. The filtrate is concentratedin vacuo to a viscous oil that is distributed between dichloromethaneand H₂O. The organic phase is dried (MgSO₄) and concentrated to an oilthat is purified by flash silica gel chromatography eluting first withdichloromethane, then with dichloromethane:MeOH (98:2). The productfractions are combined and concentrated in vacuo to leave4-chloro-6-methoxy-9H-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidine(667 mg, 80%) as a yellow oil. ¹H NMR (CDCl₃): δ8.75 (1H, s), 7.87 (1H,d, J=2.4 Hz), 7.47 (1H, d, J=8.9 Hz), 7.25 (1H, dd, J=8.9, 2.4 Hz), 4.50(2H, t, J=7.2 Hz), 3.96 (3H, s), 2.86 (2H, t, J=7.1 Hz), 2.59 (4H, q,J=7.1 Hz), 0.96 (6H, t, J=7.1 Hz).

4-(3-Bromoanilino)-6-methoxy-9H-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidinebishydrochloride. A solution of4-chloro-6-methoxy-9H-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidine(660 mg, 1.98 mmol), 3-bromoaniline (0.52 mL, 4.8 mmol, 0.25 mL of asolution of 2-propanol that is 8.5 molar in HCl, andN,N-dimethylacetamide (4 mL) is heated at 120° C. under N₂ for 2 h. Thesolution is concentrated in vacuo and the residue is distributed betweendichloromethane and 1% aqueous sodium hydroxide. The dichloromethanephase is washed with H₂O, dried (MgSO₄), and concentrated to an oil thatis purified by flash silica gel chromatography eluting first with EtOAc,then EtOAc:MeOH:triethylamine (95:5:1). The product fractions arecombined and concentrated to leave an oil that is stored at roomtemperature overnight. The semisolid is treated with an excess of asolution of 2-propanol that is 8.5 molar in HCl. After storage forseveral hours at room temperature, the solids are collected byfiltration, washed with 2-propanol, and dried to leave4-(3-bromoanilino)-6-methoxy-9H-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidine(727 mg, 650%) as a salt with 2.1 equivalents of HCl and solvated with0.9 equivalent of H₂O. ¹H NMR (DMSO): δ10.55 (1H, br s, exchanges withD₂O), 9.28 (1H, br s, exchanges with D₂O), 8.55 (1H, s), 8.02 (1H, d,J=2.2 Hz), 7.99 (1H, s), 7.84 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=7.2 Hz),7.39-7.32 (2H, m), 7.21 (1H,dd, J=8.9, 2.2 Hz), 5.30 (3H, br s,exchanges with D₂O), 4.85 (2H, t, J=7.2 Hz), 3.90 (3H, s), 3.48 (2H, dd,J=12.2, 6.4 Hz); 3.35-3.21 (4H, m); 1.23 (6H, t, J=7.2 Hz).

EXAMPLE 34 4-(3-Bromoanilino)benzofurano[3,2-d]pyrimidine

Methyl 2-(2-cyanophenoxy)ethanoate. Methyl bromoacetate (1.95 mL, 20mmol) is added dropwise to a solution of 2-cyanophenol (2.38 g, 20mmol), and K₂CO₃ (2.78 g, 20.1 mmol) in acetone (100 mL) stirred underN₂ at 25° C. After 24 h, the solid is filtered off and the filtrate isconcentrated in vacuo and the residue is dried in a vacuum oven to givemethyl 2-(2-cyanophenoxy)ethanoate (3.82 g, 100%) as a beige solid. ¹HNMR (DMSO) δ7.76 (1H, dd, J=7.6, 1.7 Hz), 7.64 (1H, dt, J_(d)=1.6 Hz,J_(t)=8.0 Hz), 7.20˜7.10 (2H, m), 5.04 (2H, brs), 3.70 (3H, s).

Methyl 3-aminobenzo[b]furan-2-carboxylate. A solution of methyl2-(2-cyanophenoxy)ethanoate (3.82 g, 20 mmol) in DMSO (40 mL) is addeddropwise to a suspension of NaH (0.84 g, 21 mmol) and DMSO (10 mL)stirred under N₂ at 25° C. After 10 min the mixture is poured onto icewater and extracted with ether. The combined extracts are washed withwater, saturated brine and dried (MgSO₄). After removal of the solventunder reduced pressure, methyl 3-aminobenzo[b]furan-2-carboxylate (2.15g, 56%) is obtained as a yellow solid. ¹H NMR (DMSO) δ7.95 (1H, d, J=7.7Hz), 7.48 (2H, d, J=3.4 Hz), 7.29-7.22 (1H, m), 6.40 (2H, brs), 3.80(3H, s).

3H-Benzofurano[3,2-d]pyrimid-4-one. A solution of methyl3-aminobenzo[b]furan-2-carboxylate (0.28 g, 1.36 mmol) in formamide (5mL) is heated at 135 C. for 4 h, then the temperature is raised to 170C. After 4 h the reaction is cooled to 25° C. and a dark purple solidprecipitates. The solid is collected by vacuum filtration and air driedto give 3H-benzofurano[3,2-d]pyrimid-4-one (118 mg, 46.6%). ¹H NMR(DMSO) δ13.0 (1H, brs), 8.25 (1H, s), 8.05 (1H, d, J=8.1 Hz), 7.84 (1H,d, J=8.3 Hz), 7.68 (1H, t, J=7.7 Hz), 7.51 (1H, t, J=7.7 Hz).

4-Chlorobenzofurano[3.2-d]pyrimidine. DMF (0.23 mL, 3.1 mmol) is addeddropwise to a solution of (COCl)₂ (0.28 mL, 3.1 mmol) in1,2-dichloroethane (15 mL) at 25° C. After gas evolution ceases,3H-benzofurano[3,2-d]pyrimid-4-one (113 mg, 0.61 mmol) is added. Theresulting mixture is heated at reflux for 1 h. After the reaction hascooled to 25° C., water is added and the resulting mixture is extractedwith CHCl₃. The combined extracts are washed with water, saturated brineand dried (MgSO₄). The solvent is removed under reduced pressure to give4-chlorobenzofurano[3,2-d]pyrimidine (116 mg, 93%) as a yellow solid. ¹HNMR (DMSO) δ9.08 (1H, s), 8.30 (1H, d. J=8.1 Hz), 8.02 (1H, d, J=8.5Hz), 7.90, (1H, dt, J_(d)=1.3 Hz, J_(t)=7.1 Hz), 7.64 (1H, dt, J_(d)=1.0Hz, J_(t)=7.8 Hz).

4-(3-Bromoanilino)benzofurano[3,2-d]pyrimidine. A mixture of4-chlorobenzofurano[3,2-d]pyrimidine (116 mg, 0.57 mmol) and3-bromoaniline (0.07 mL, 0.6 mmol) is heated at 135° C. under N₂ instirred 2-ethoxyethanol for 3 h. The mixture precipitates upon cooling,and the solid is collected and recrystallized from EtOH to give4-(3-bromoanilino)benzofurano[3,2-d]pyrimidine (15.7 mg, 8%). ¹H NMR(DMSO) δ10.35 (1H, s), 8.73 (1H, s), 8.34 (1H, t, J=1.9 Hz), 8.17 (1H,ddd, J=7.2, 1.2, 0.7 Hz), 7.93 (1H, ddd, J=8.2, 2.2, 1.0 Hz), 7.88 (1H,d, J=8.4 Hz), 7.77 (1H, dt, J_(d)=1.4 Hz, J_(t)=7.2 Hz), 7.56 (1H, dt,J_(d)=0.8 Hz, J_(t)=8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.27 (1H, ddd,J=8.0, 2.0, 1.0 Hz).

The pharmaceutical compositions of the invention can take any of a widevariety of oral and parenteral dosage forms. The dosage forms compriseas the active components an inhibitor as defined previously.

For preparing pharmaceutical compositions, one uses inert,pharmaceutically acceptable carriers that can be either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets, and suppositories. A solid carrier can be one or moresubstances which may also act as dilutents, flavoring agents,solubilizers, lubricants, suspending agents, binders, or tabletdisintegrating agents; it can also be an encapsulating material. Inpowders, the carrier is a finely divided solid which is in admixturewith the finely divided active compounds. In the tablet, the activecompounds are mixed with carrier having the necessary binding propertiesin suitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain from 5% or 10% to about 70% ofactive ingredients. Suitable solid carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compounds withencapsulating materials as carrier, providing a capsule in which theactive components (with or without other carriers) are surrounded bycarrier, which are thus in association with it. Similarly, cachets areincluded. Tablets, powders, cachets, and capsules can be used as soliddosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by dissolving the active componentin water and adding suitable colorants, flavors, stabilizing, andthickening agents as desired. Aqueous suspensions suitable for oral usecan be made by dispersing the finely divided active components in waterwith viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-knownsuspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation may be subdivided into unit doses containingappropriate quantities of inhibitor and other anti-cancer materialsindividually or as a combination, i.e., in a mixture. The unit dosageform can be a packaged preparation, the package containing discretequantities of preparation, for example, packeted tablets, capsules, andpowders in vials or ampoules. The unit dosage form can also be acapsule, cachet, or tablet itself or it can be the appropriate number ofany of these in packaged form. Additionally, the unit dosage form may bea dividable form having an inhibitor in one part and other anti-cancermaterials in the other part, such as, a dividable capsule, a dividablepackage, or a two-part ampoule, vial or the like.

The quantity of an inhibitor in unit dosages of preparation may bevaried or adjusted from about 0.01 mg/kg to 100.0 mg/kg, preferably 0.03mg/kg to less than 1.0 mg/kg of inhibitor.

The pharmaceutical compositions preferably are constituted so that theycan be administered parenterally or orally. Solutions of the activecompounds as free bases and free acids or pharmaceutically acceptablesalts can be prepared in water suitable mixed with a surfactant such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of the microorganisms such as bacteria and fungi.The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion, and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, paragens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferred to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions of agents delaying absorption, for example,gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousother ingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients, into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of the sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze-drying technique whichyields a powder of active ingredients plus an additional desiredingredient from a previously sterile-filtered solution thereof.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuitable as unitary dosages for the mammalian subjects to be treated;each unit containing a predetermined quantity of active materialscalculated to produce the desired therapeutic effect in association withthe required pharmaceutical carrier. The specification for the noveldosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the active materials andthe particular therapeutic effect to be achieved, and (b) the limitationinherent in the art of compounding such active materials for thetreatment of disease in living subjects having a diseased condition inwhich bodily health is impaired as herein disclosed in detail.

The principal active ingredients are compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedisclosed. A unit parenteral dosage form can, for example, contain theprincipal active compound, i.e. an inhibitor, in amounts ranging fromabout 0.5 to about 100 mg, with from about 0.1 to 50 mg being preferred.The daily parenteral doses for mammalian subjects to be treated rangesfrom 0.01 mg/kg to 10 mg/kg of the inhibitor. The preferred daily dosagerange is 0.1 mg/kg to 1.0 mg/kg.

For oral dosages, the daily amount may range from 0.01 mg of activecompound/kg of mammalian subject to 100 mg/kg, preferably 0.1 to 10mg/kg of subject.

The inhibitor described above may form commonly known, pharmaceuticallyacceptable salts such as alkali metal and other common basic salts oracid addition salts, etc. References to the base substances aretherefore intended to include those common salts known to besubstantially equivalent to the parent compound and hydrates thereof.

The active compounds described herein are capable of further formingboth pharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the active compoundsinclude salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge, S. M. et al,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 66, pp. 1-19(1977)).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. Preferably, anactive compound can be converted to an acidic salt by treating with anaqueous solution of the desired acid, such that the resulting pH is lessthan 4. The solution can be passed through a C18 cartridge to absorb thecompound, washed with copious amounts of water, the compound eluted witha polar organic solvent such as, for example, methanol, acetonitrile,and the like, and isolated by concentrating under reduced pressurefollowed by lyophilization. The free base form may be regenerated bycontacting the salt form with a base and isolating the free base in theconventional manner. The free base forms differ from their respectivesalt forms somewhat in certain physical properties such as solubility inpolar solvents, but otherwise the salts are equivalent to theirrespective free base for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, Journalof Pharmaceutical Science, 66, pp. 1-19 (1977)).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. Preferably, anactive compound can be converted to a base salt by treating with anaqueous solution of the desired base, such that the resulting pH isgreater than 9. The solution can be passed through a C18 cartridge toabsorb the compound, washed with copious amounts of water, the compoundeluted with a polar organic solvent such as, for example, methanol,acetonitrile and the like, and isolated by concentrating under reducedpressure followed by lyophilization. The free acid form may beregenerated by contacting the salt form with an acid and isolating thefree acid in the conventional manner. The free acid forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but otherwise the salts are equivalentto their respective free acids for purposes of the present invention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and such it center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

While the forms of the invention herein constitute presently preferredembodiments, many others are possible. It is not intended herein tomention all of the possible equivalent forms or ramifications of theinvention. It is understood that the terms used herein are merelydescriptive rather than limiting and that various changes may be madewithout departing from the spirit or scope of the invention.

What is claimed is:
 1. A method of inhibiting epidermal growth factorreceptor tyrosine kinase by treating, with an effective inhibitingamount, a mammal, in need thereof, a compound of the formula:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle; A, B, D and E can all be carbon, or up to two of them can benitrogen, whereupon the remaining atoms must be carbon, or any twocontiguous positions in A-E can be a single heteroatom, N, O or S,forming a five membered fused ring, in which case one of the tworemaining atoms must be carbon, and the other can be either carbon ornitrogen, except that the case where A and B taken together, and D and Etaken separately are all three nitrogen atoms; X=O, S, NH or NR⁹, suchthat R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂, lower alkoxy (1-4carbon atoms) or lower monoalkylamino (1-4 carbon atoms); R¹=H or loweralkyl; n=0, 1 or 2; if n=2, R¹ can be independently H or lower alkyl(1-4 carbon atoms) on either linking carbon atom, and both R and Sstereocentres on either linker are included; R² is lower alkyl (1-4carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbonatoms), cycloalkoxy (3-8 carbon atoms), nitro, halo, lowerperfluoroalkyl (1-4 carbon atoms), hydroxy, lower acyloxy (1-4 carbonatoms; —O—C(O)—R), amino, lower mono or dialkylamino (1-4 carbon atoms),lower mono or dicycloalkylamino (3-8 carbon atoms), hydroxymethyl, loweracyl (1-4 carbon atoms; —C(O)R), cyano, lower thioalkyl (1-4 carbonatoms), lower sulfinylalkyl (1-4 carbon atoms), lower sulfonylalkyl (1-4carbon atoms), thiocycloalkyl (3-8 carbon atoms), sulfinylcycloalkyl(3-8 carbon atoms), sulfonylcycloalkyl (3-8 carbon atoms), mercapto,lower alkoxycarbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbonatoms), lower alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbonatoms), lower alkynyl (2-4 carbon atoms), or two R² taken together canform a carbocyclic ring of 5-7 members; and m=0-3, wherein Ar is phenyl,thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl,oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl and quinazolinyl; R³, R⁴, R⁵ and R⁶ areindependently not present, H, lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lowermono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8carbon atoms), carbonato (—OC(O)OR) where R is alkyl of from 1-4 carbonatoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido orN- or O-linked urethane any one of which is optionally substituted bymono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbonatoms); lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N- and/orN′- mono- or di lower alkylhydrazino (1-4 carbon atoms), lower acylamino(1-4 carbon atoms), hydroxylamino, N- and/or O- mono- or di loweralkylhydroxylamino (1-4 carbon atoms), or any two substituents oncontiguous carbon atoms taken together can be methylene-, ethylene- orpropylenedioxy, or taken together form a fused pyrrolidine,tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino orthiomorpholino ring; R⁷ and R⁸ can be independently as appropriate, notpresent, lone pairs of electrons, H, or lower alkyl (1-4 carbon atoms);any lower alkyl group substituent on any of the substituents in R³-R⁸which contain such a moiety can be optionally substituted with one ormore of hydroxy, amino, lower monoalkylamino, lower dialkylamino,N-pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino,N-thiomorpholino or N-piperazino groups; if one or two of A through Eare N, then if any of R³-R⁶ is on a neighboring C atom to one of the Natoms, that substituent cannot be either OH or SH; and R¹⁰ is H or loweralkyl (1-4 carbon atoms), amino or lower mono-or dialkylamino (1-4carbon atoms); if any of the substitutents R¹, R², R³ or R⁴ containchiral centers, or in the case of R¹ create chiral centers on thelinking atoms, then all stereoisomers thereof both separately and asracemic and/or diastereoisomeric mixtures are included: A) with theproviso that the ring containing A-E is aromatic; B) and with theproviso that if A and B taken together and E are nitrogen, and ifneither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=H andAr=Ph, then one of the imidazole nitrogen atoms must have a substituentfrom the R³-R⁶ group other than lone pair or hydrogen; C) and with theproviso that if A-E are carbon, and Y is a bond, and Z is sulfur, andX=NH, and n=0, then Ar cannot be unsubstituted phenyl, unsubstituted orsubstituted pyridyl or unsubstituted or substituted pyrimidyl; D) withthe proviso that if A-E are carbon, Y and Z cannot be both carbon or oneethylidene and the other a bond, unless at least one of R³ -R⁶is nothydrogen; E) with the proviso that if A-E are carbon one of Y and Zcannot be nitrogen, substituted with hydrogen, and the other a bond; ora pharmaceutical salt or hydrate thereof.
 2. The method of claim 1wherein n=0 or 1, with one of A & B or D & E taken together as nitrogen,the remaining pair both being carbon, along with Y and Z, X=NH, Ar abenzene ring, optionally substituted, and R⁵-R⁶ hydrogen or lower alkylif on nitrogen.
 3. The method of claim 1 wherein any of the substituentsR¹, R², R³ or R⁴ contain chiral centers, or in the case of R¹ createchiral centers on the linking atoms, then all stereoisomers thereof bothseparately and as racemic and/or diastereoisomeric mixtures are includedtherein.
 4. A method of inhibiting Erb-B2 or Erb-B3 or Erb-B4 receptortyrosine kinase by treating, with an effective inhibiting amount, amammal, in need thereof, a compound of the formula:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle; A, B, D and E can all be carbon, or up to two of them can benitrogen, whereupon the remaining atoms must be carbon, or any twocontiguous positions in A-E can be a single heteroatom, N, O or S,forming a five membered fused ring, in which case one of the tworemaining atoms must be carbon, and the other can be either carbon ornitrogen, except that the case where A and B taken together, and D and Etaken separately are all three nitrogen atoms; X=O, S, NH or NR⁹, suchthat R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂, lower alkoxy (1-4carbon atoms) or lower monoalkylamino (1-4 carbon atoms); R¹=H or loweralkyl; n=0, 1 or 2; if n=2, R¹ can be independently H or lower alkyl oneither linking carbon atom, and both R and S stereocentres on eitherlinker are included; R² is lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), nitro, halo, lower perfluoroalkyl (1-4 carbon atoms),hydroxy, lower acyloxy (1-4 carbon atoms; —O—C(O)—R), amino, lower monoor dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8carbon atoms), hydroxymethyl, lower acyl (1-4 carbon atoms; —C(O)R),cyano, lower thioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4carbon atoms), lower sulfonylalkyl (1-4 carbon atoms), thiocycloalkyl(3-8 carbon atoms), sulfinylcycloalkyl (3-8 carbon atoms),sulfonylcycloalkyl (3-8 carbon atoms), mercapto, lower alkoxycarbonyl(1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbon atoms), loweralkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), loweralkynyl (2-4 carbon atoms), or two R² taken together can form acarbocyclic ring of 5-7 members; and m=0-3, wherein Ar is phenyl,thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl,oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl and quinazolinyl; R³, R⁴, R⁵ and R⁶ areindependently not present, H, lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lowermono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8carbon atoms), carbonato (—OC(O)OR) where R is alkyl of from 1-4 carbonatoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido orN- or O-linked urethane any one of which is optionally substituted bymono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbonatoms); lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N′-loweralkylhydrazino (1-4 carbon atoms), lower acylamino (1-4 carbon atoms),hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms), or takentogether can be methylene-, ethylene-or propylenedioxy, or takentogether form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholino or thiomorpholino ring; R⁷ and R⁸ can beindependently as appropriate, lone pairs of electrons, H, or lower alkyl(1-4 carbon atoms); any lower alkyl group substituent on any of thesubstituents in R³-R⁸ which contain such a moiety can be optionallysubstituted with one or more of hydroxyl, amino, lower monoalkylamino,lower dialkylamino, N-pyrrolidyl, N-piperidinyl, N-pyridinium,N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two ofA through E are N, then if any of R³-R⁶ is on a neighboring C atom toone of the N atoms, that substituent cannot be either OH or SH; and R¹⁰is H or lower alkyl (1-4 carbon atoms), amino or lower mono- ordialkylamino (1-4 carbon atoms); if any of the substitutents R¹, R², R³or R⁴ contain chiral centers, or in the case of R¹ create chiral centerson the linking atoms, then all stereoisomers thereof both separately andas racemic and/or diastereoisomeric mixtures are included: A) with theproviso that the ring containing A-E is aromatic; B) and with theproviso that if A and B taken together and E are nitrogen, and ifneither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=H andAr=Ph, then one of the imidazole nitrogen atoms must have a substituentfrom the R³-R⁶ group other than lone pair or hydrogen; C) and with theproviso that if A-E are carbon, and Y is a bond, and Z is sulfur, andX=NH, and n=0, then Ar cannot be unsubstituted phenyl, unsubstituted orsubstituted pyridyl or unsubstituted or substituted pyrimidyl; D) withthe proviso that if A-E are carbon, Y and Z cannot be both carbon or oneethylidene and the other a bond, unless at least one of R³-R⁶is nothydrogen; E) with the proviso that if A-E are carbon one of Y and Zcannot be nitrogen, substituted with hydrogen, and the other a bond; ora pharmaceutical salt or hydrate thereof.
 5. A method of treating cancerby treating, with an effective cancer inhibiting amount, a mammal, inneed thereof, a compound of the formula:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle; A, B, D and E can all be carbon, or up to two of them can benitrogen, whereupon the remaining atoms must be carbon, or any twocontiguous positions in A-E can be a single heteroatom, N, O or S,forming a five membered fused ring, in which case one of the tworemaining atoms must be carbon, and the other can be either carbon ornitrogen, except that the case where A and B taken together, and D and Etaken separately are all three nitrogen atoms; X=O, S, NH or NR⁹, suchthat R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂, lower alkoxy (1-4carbon atoms) or lower monoalkylamino (1-4 carbon atoms); R¹=H or loweralkyl; n=0, 1 or 2; if n=2, R¹ can be independently H or lower alkyl(1-4 carbon atoms) on either linking carbon atom, and both R and Sstereocentres on either linker are included; R² is lower alkyl (1-4carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbonatoms), cycloalkoxy (3-8 carbon atoms), nitro, halo, lowerperfluoroalkyl (1-4 carbon atoms), hydroxy, lower acyloxy (1-4 carbonatoms; —O—C(O)—R), amino, lower mono or dialkylamino (1-4 carbon atoms),lower mono or dicycloalkylamino (3-8 carbon atoms), hydroxymethyl, loweracyl (1-4 carbon atoms; —C(O)R), cyano, lower thioalkyl (1-4 carbonatoms), lower sulfinylalkyl (1-4 carbon atoms), lower sulfonylalkyl (1-4carbon atoms), thiocycloalkyl (3-8 carbon atoms), sulfinylcycloalkyl(3-8 carbon atoms), sulfonylcycloalkyl (3-8 carbon atoms), mercapto,lower alkoxycarbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbonatoms), lower alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbonatoms), lower alkynyl (2-4 carbon atoms), or two R² taken together canform a carbocyclic ring of 5-7 members; and m=0-3, wherein Ar is phenyl,thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl,oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl and quinazolinyl; R³, R⁴, R⁵ and R⁶ areindependently not present, H, lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lowermono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8carbon atoms), carbonato (—OC(O)OR) where R is alkyl of from 1-4 carbonatoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido orN- or O-linked urethane any one of which is optionally substituted bymono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbonatoms); lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N′-loweralkylhydrazino (1-4 carbon atoms), lower acylamino (1-4 carbon atoms),hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms), or takentogether can be methylene-, ethylene- or propylenedioxy, or takentogether form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholino or thiomorpholino ring; R⁷ and R⁸ can beindependently as appropriate, lone pairs of electrons, H, or lower alkyl(1-4 carbon atoms); any lower alkyl group substituent on any of thesubstituents in R³-R⁸ which contain such a moiety can be optionallysubstituted with one or more of hydroxy, amino, lower monoalkylamino,lower dialkylamino, N-pyrrolidyl, N-piperidinyl, N-pyridinium,N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two ofA through E are N, then if any of R³-R⁶ is on a neighboring C atom toone of the N atoms, that substituent cannot be either OH or SH; and R¹⁰is H or lower alkyl (1-4 carbon atoms), amino or lower mono- ordialkylamino (1-4 carbon atoms); if any of the substitutents R¹, R², R³or R⁴ contain chiral centers, or in the case of R¹ create chiral centerson the linking atoms, then all stereoisomers thereof both separately andas racemic and/or diastereoisomeric mixtures fu are included: A) withthe proviso that the ring containing A-E is aromatic; B) and with theproviso that if A and B taken together and E are nitrogen, and ifneither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=H andAr=Ph, substituent from the R³-R⁶ group other than lone pair orhydrogen; C) and with the proviso that if A-E are carbon, and Y is abond, and Z is sulfur, and X=NH, and n=0, then Ar cannot beunsubstituted phenyl, unsubstituted or substituted pyridyl orunsubstituted or substituted pyrimidyl; D) with the proviso that if A-Eare carbon, Y and Z cannot be both carbon or one ethylidene and theother a bond, unless at least one of R -R is not hydrogen; E) with theproviso that if A-E are carbon one of Y and Z cannot be nitrogen,substituted with hydrogen, and the other a bond; or a pharmaceuticalsalt or hydrate thereof.
 6. A method of treating psoriasis by treating,with an effective psoriasis inhibiting amount, a mammal, in needthereof, a compound of the formula:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle; A, B, D and E can all be carbon, or up to two of them can benitrogen, whereupon the remaining atoms must be carbon, or any twocontiguous positions in A-E can be a single heteroatom, N, O or S,forming a five membered fused ring, in which case one of the tworemaining atoms must be carbon, and the other can be either carbon ornitrogen, except that the case where A and B taken together, and D and Etaken separately are all three nitrogen atoms; X=O, S, NH or NR⁹, suchthat R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂, lower alkoxy (1-4carbon atoms) or lower monoalkylamino (1-4 carbon atoms); R¹=H or loweralkyl; n=0, 1 or 2; if n=2, R¹ can be independently H or lower alkyl oneither linking carbon atom, and both R and S stereocentres on eitherlinker are included; R² is lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), nitro, halo, lower perfluoroalkyl (1-4 carbon atoms),hydroxy, lower acyloxy (1-4 carbon atoms; —O—C(O)—R), amino, lower monoor dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8carbon atoms), hydroxymethyl, lower acyl (1-4 carbon atoms; —C(O)R),cyano, lower thioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4carbon atoms), lower sulfonylalkyl (1-4 carbon atoms), thiocycloalkyl(3-8 carbon atoms), sulfinylcycloalkyl (3-8 carbon atoms),sulfonylcycloalkyl (3-8 carbon atoms), mercapto, lower alkoxycarbonyl(1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbon atoms), loweralkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), loweralkynyl (2-4 carbon atoms), or two R² taken together can form acarbocyclic ring of 5-7 members; and m=0-3, wherein Ar is phenyl,thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl,oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl and quinazolinyl; R³, R⁴, R⁵ and R⁶ areindependently not present, H, lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lowermono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8carbon atoms), carbonate (—OC(O)OR) where R is alkyl of from 1-4 carbonatoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido orN- or O-linked urethane any one of which is optionally substituted bymono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbonatoms); lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N′-loweralkylhydrazino (1-4 carbon atoms), lower acylamino (1-4 carbon atoms),hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms), or takentogether can be methylene-, ethylene- or propylenedioxy, or takentogether form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholino or thiomorpholino ring; R⁷ and R⁸ can beindependently as appropriate, lone pairs of electrons, H, or lower alkyl(1-4 carbon atoms); any lower alkyl group substituent on any of thesubstituents in R³-R⁸ which contain such a moiety can be optionallysubstituted with one or more of hydroxy, amino, lower monoalkylamino,lower dialkylamino, N-pyrrolidyl, N-piperidinyl, N-pyridinium,N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two ofA through E are N, then if any of R³-R⁶ is on a neighboring C atom toone of the N atoms, that substituent cannot be either OH or SH; and R¹⁰is H or lower alkyl (1-4 carbon atoms), amino or lower mono- ordialkylamino (1-4 carbon atoms); if any of the substitutents R¹, R², R³or R⁴ contain chiral centers, or in the case of R¹ create chiral centerson the linking atoms, then all stereoisomers thereof both separately andas racemic and/or diastereoisomeric mixtures are included: A) with theproviso that the ring containing A-E is aromatic; B) and with theproviso that if A and B taken together and E are nitrogen, and ifneither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=H andAr=Ph, then one of the imidazole nitrogen atoms must have a substituentfrom the R³-R⁶ group other than lone pair or hydrogen; C) and with theproviso that if A-E are carbon, and Y is a bond, and Z is sulfur, andX=NH, and n=0, then Ar cannot be unsubstituted phenyl, unsubstituted orsubstituted pyridyl or unsubstituted or substituted pyrimidyl; D) withthe proviso that if A-E are carbon, Y and Z cannot be both carbon or oneethylidene and the other a bond, unless at least one of R³-R⁶ is nothydrogen; E) with the proviso that if A-E are carbon one of Y and Zcannot be nitrogen, substituted with hydrogen, and the other a bond; ora pharmaceutical salt or hydrate thereof.
 7. A contraceptive compositioncomprising a contraceptively effective amount of a compound of thefollowing formula in admixture with a contraceptively acceptableexcipient, diluent or carrier:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle; A, B, D and E can all be carbon, or up to two of them can benitrogen, whereupon the remaining atoms must be carbon, or any twocontiguous positions in A-E can be a single heteroatom, N, O or S,forming a five membered fused ring, in which case one of the tworemaining atoms must be carbon, and the other can be either carbon ornitrogen, except that the case where A and B taken together, and D and Etaken separately are all three nitrogen atoms; X=O, S, NH or NR⁹, suchthat R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂, lower alkoxy (1-4carbon atoms) or lower monoalkylamino (1-4 carbon atoms); R¹=H or loweralkyl; n=0, 1 or 2; if n=2, R¹ can be independently H or lower alkyl oneither linking carbon atom, and both R and S stereocentres on eitherlinker are included; R² is lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), nitro, halo, lower perfluoroalkyl (1-4 carbon atoms),hydroxy, lower acyloxy (1-4 carbon atoms; —O—C(O)—R), amino, lower monoor dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8carbon atoms), hydroxymethyl, lower acyl (1-4 carbon atoms; —C(O)R),cyano, lower thioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4carbon atoms), lower sulfonylalkyl (1-4 carbon atoms), thiocycloalkyl(3-8 carbon atoms), sulfinylcycloalkyl (3-8 carbon atoms),sulfonylcycloalkyl (3-8 carbon atoms), mercapto, lower alkoxycarbonyl(1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbon atoms), loweralkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), loweralkynyl (2-4 carbon atoms), or two R² taken together can form acarbocyclic ring of 5-7 members; and m=0-3, wherein Ar is phenyl,thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl,oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl and quinazolinyl; R³, R⁴, R⁵ and R⁶ areindependently not present, H, lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lowermono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8carbon atoms), carbonato (—OC(O)OR) where R is alkyl of from 1-4 carbonatoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido orN- or O-linked urethane any one of which is optionally substituted bymono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbonatoms); lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N′-loweralkylhydrazino (1-4 carbon atoms), lower acylamino (1-4 carbon atoms),hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms), or takentogether can be methylene-, ethylene- or propylenedioxy, or takentogether form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholino or thiomorpholino ring; R⁷ and R⁸ can beindependently as appropriate, lone pairs of electrons, H, or lower alkyl(1-4 carbon atoms); any lower alkyl group substituent on any of thesubstituents in R³-R⁸ which contain such a moiety can be optionallysubstituted with one or more of hydroxy, amino, lower monoalkylamino,lower dialkylamino, N-pyrrolidyl, N-piperidinyl, N-pyridinium,N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two ofA through E are N, then if any of R³-R⁶ is on a neighboring C atom toone of the N atoms, that substituent cannot be either OH or SH; and R¹⁰is H or lower alkyl (1-4 carbon atoms), amino or lower mono- ordialkylamino (1-4 carbon atoms); if any of the substitutents R¹, R², R³or R⁴ contain chiral centers, or in the case of R¹ create chiral centerson the linking atoms, then all stereoisomers thereof both separately andas racemic and/or diastereoisomeric mixtures are included: A) with theproviso that the ring containing A-E is aromatic; B) and with theproviso that if A and B taken together and E are nitrogen, and ifneither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=H andAr=Ph, then one of the imidazole nitrogen atoms must have a substituentfrom the R³-R⁶ group other than lone pair or hydrogen; C) and with theproviso that if A-E are carbon, and Y is a bond, and Z is sulfur, andX=NH, and n=0, then Ar cannot be unsubstituted phenyl, unsubstituted orsubstituted pyridyl or unsubstituted or substituted pyrimidyl; D) withthe proviso that if A-E are carbon, Y and Z cannot be both carbon or oneethylidene and the other a bond, unless at least one of R³-R⁶ is nothydrogen; E) with the proviso that if A-E are carbon one of Y and Zcannot be nitrogen, substituted with hydrogen, and the other a bond; ora pharmaceutical salt or hydrate thereof.
 8. A method of treatingpancreatitis by treating, with an effective amount inhibiting a mammal,in need thereof, a compound of the formula:

wherein: 1) Y and Z are both C (carbon), both N or one N and the otherC, in which case the ring structure is a linearly fused 6,6 (5 or 6)tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Yor Z is simply a bond between the two aromatic rings, then the ringstructure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z isN, O or S, whereupon the other one of Y or Z is simply a bond betweenthe two aromatic rings, then the ring structure is a fused 6,5 (5 or 6)tricycle; A, B, D and E can all be carbon, or up to two of them can benitrogen, whereupon the remaining atoms must be carbon, or any twocontiguous positions in A-E can be a single heteroatom, N, O or S,forming a five membered fused ring, in which case one of the tworemaining atoms must be carbon, and the other can be either carbon ornitrogen, except that the case where A and B taken together, and D and Etaken separately are all three nitrogen atoms; X=O, S, NH or NR⁹ ₁ suchthat R⁹=lower alkyl (1-4 carbon atoms), OH, NH₂, lower alkoxy (1-4carbon atoms) or lower monoalkylamino (1-4 carbon atoms); R¹=H or loweralkyl; n=0, 1 or 2; if n=2, R¹ can be independently H or lower alkyl(1-4 carbon atoms) on either linking carbon atom, and both R and Sstereocentres on either linker are included; R² is lower alkyl (1-4carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbonatoms), cycloalkoxy (3-8 carbon atoms), nitro, halo, lowerperfluoroalkyl (1-4 carbon atoms), hydroxy, lower acyloxy (1-4 carbonatoms; —O—C(O)—R), amino, lower mono or dialkylamino (1-4 carbon atoms),lower mono or dicycloalkylamino (3-8 carbon atoms), hydroxymethyl, loweracyl (1-4 carbon atoms; —C(O)R), cyano, lower thioalkyl (1-4 carbonatoms), lower sulfinylalkyl (1-4 carbon atoms), lower sulfonylalkyl (1-4carbon atoms), thiocycloalkyl (3-8 carbon atoms), sulfinylcycloalkyl(3-8 carbon atoms), sulfonylcycloalkyl (3-8 carbon atoms), mercapto,lower alkoxycarbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbonatoms), lower alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbonatoms), lower alkynyl (2-4 carbon atoms), or two R² taken together canform a carbocyclic ring of 5-7 members; and m=0-3, wherein Ar is phenyl,thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl,oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl and quinazolinyl; R³, R⁴, R⁵ and R⁶ areindependently not present, H, lower alkyl (1-4 carbon atoms), cycloalkyl(3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lowermono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8carbon atoms), carbonato (—OC(O)OR) where R is alkyl of from 1-4 carbonatoms or cycloalkyl of from 3-8 carbon atoms; or ureido or thioureido orN- or O-linked urethane any one of which is optionally substituted bymono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbonatoms); lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbonatoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, N′-loweralkylhydrazino (1-4 carbon atoms), lower acylamino (1-4 carbon atoms),hydroxylamino, lower O-alkylhydroxylamino (1-4 carbon atoms), or takentogether can be methylene-, ethylene- or propylenedioxy, or takentogether form a fused pyrrolidine, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholino or thiomorpholino ring; R⁷ and R⁸ can beindependently as appropriate, lone pairs of electrons, H, or lower alkyl(1-4 carbon atoms); any lower alkyl group substituent on any of thesubstituents in R³-R⁸ which contain such a moiety can be optionallysubstituted with one or more of hydroxy, amino, lower monoalkylamino,lower dialkylamino, N-pyrrolidyl, N-piperidinyl, N-pyridinium,N-morpholino, N-thiomorpholino or N-piperazino groups; if one or two ofA through E are N, then if any of R³-R⁶ is on a neighboring C atom toone of the N atoms, that substituent cannot be either OH or SH; and R¹⁰is H or lower alkyl (1-4 carbon atoms), amino or lower mono- ordialkylamino (1-4 carbon atoms); if any of the substitutents R¹, R², R³or R⁴ contain chiral centers, or in the case of R¹ create chiral centerson the linking atoms, then all stereoisomers thereof both separately andas racemic and/or diastereoisomeric mixtures are included: A) with theproviso that the ring containing A-E is aromatic; B) and with theproviso that if A and B taken together and E are nitrogen, and ifneither Y nor Z is a heteroatom, and if X=NH, and n=1, and R¹=H andAr=Ph, then one of the imidazole nitrogen atoms must have a substituentfrom the R³—R⁶ group other than lone pair or hydrogen; C) and with theproviso that if A-E are carbon, and Y is a bond, and Z is sulfur, andX=NH, and n=0, then Ar cannot be unsubstituted phenyl, unsubstituted orsubstituted pyridyl or unsubstituted or substituted pyrimidyl; D) withthe proviso that if A-E are carbon, Y and Z cannot be both carbon or oneethylidene and the other a bond, unless at least one of R³-R⁶is nothydrogen; E) with the proviso that if A-E are carbon one of Y and Zcannot be nitrogen, substituted with hydrogen, and the other a bond; ora pharmaceutical salt or hydrate thereof.
 9. The method of claim 1having the ring structure:


10. A compound selected from the group consisting of4-(3-Bromoanilino)benzo[g]quinazoline;4-([R]-1-Phenylethylamino)benzo[g]quinazoline;4-(3-Bromoanilino)pyrrolo[3,2-g]quinazoline;4-(3-Bromoanilino)thiazolo[4,5-g]quinazoline;4-(3-Bromoanilino)imidazolo [4,5-h]quinazoline;4-(3-Bromoanilino)thiazolo[4′5′:4,5]thieno[3,2-d]pyrimidine;4-(3-Bromoanilino)indolo[3,2-d]pyrimidine; and4-(3-Bromoanilino)indolo[2,3-d]pyrimidine.